Zymeworks Inc (ZYME) 2024 Q2 法說會逐字稿

Thank you for standing by. This is the conference operator. Welcome to Zymeworks second-quarter 2024 results conference call and webcast. As a reminder, all participants are in a listen-only mode, and the conference is being recorded. (Operator Instructions)

謝謝你的支持。這是會議操作員。歡迎參加 Zymeworks 2024 年第二季業績電話會議和網路廣播。提醒一下，所有與會者都處於只聽模式，並且正在錄製會議。（操作員說明）

I would now like to turn the conference over to Shrinal Inamdar, Director of Investor Relations. Shrinal, please go ahead.

現在我想將會議交給投資者關係總監 Shrinal Inamdar。神社，請繼續。

Thank you, operator. Good afternoon, and thank you for joining our second-quarter 2024 results conference call.

謝謝你，接線生。下午好，感謝您參加我們的 2024 年第二季業績電話會議。

Before we begin, I would like to remind you that we'll be making a number of forward-looking statements during this call, including, without limitation, those forward-looking statements identified in our slides and the accompanying oral commentary. Forward-looking statements are based on our current expectations and various assumptions and are subject to the usual risks and uncertainties associated with companies in our industry and at our stage of development. For a discussion of these risks and uncertainties, we refer you to our latest SEC filings as found on our website and as filed with the SEC.

在開始之前，我想提醒您，我們將在本次電話會議期間做出一些前瞻性聲明，包括但不限於我們的幻燈片和隨附的口頭評論中確定的前瞻性聲明。前瞻性陳述基於我們目前的預期和各種假設，並受到與我們行業和發展階段的公司相關的常見風險和不確定性的影響。為了討論這些風險和不確定性，我們建議您參閱我們網站上以及向 SEC 提交的最新 SEC 文件。

In a moment, I will hand over to Bijal Desai, our VP of Finance and Strategy, who will be discussing recent corporate updates, along with our financial results for the second quarter 2024. Following this, Dr. Paul Moore, our Chief Scientific Officer, will talk about key highlights for our second quarter, including the investigation of new drug application clearances for ZW171 and ZW191 by the FDA. At the end of the call, Bijal, Paul, and Ken Galbraith, our Chair and CEO, will be available for Q&A as well as Pranshul Chauhan, Associate Medical Director for Early-Stage Development for ZW171.

稍後，我將把工作交給我們的財務和策略副總裁 Bijal Desai，他將討論最近的公司動態以及我們 2024 年第二季的財務表現。接下來，我們的首席科學官 Paul Moore 博士將談論我們第二季度的主要亮點，包括 FDA 對 ZW171 和 ZW191 新藥申請審批的調查。電話會議結束時，Bijal、Paul 和我們的主席兼執行長 Ken Galbraith 以及 ZW171 早期開發醫療副總監 Pranshul Chauhan 將出席問答環節。

As a reminder, the audio and slides from this call will also be available on the Zymeworks website later today. I will now turn the call over to Bijal.

提醒一下，本次電話會議的音訊和幻燈片也將於今天稍晚在 Zymeworks 網站上提供。我現在將把電話轉給比賈爾。

Thanks, Shrinal, and thank you, everyone, for joining us today for our second-quarter 2024 earnings call. I will begin today's call with an overview of key achievements from our development programs as well as our financial results.

謝謝 Shrinal，也謝謝大家今天參加我們的 2024 年第二季財報電話會議。我將在今天的電話會議開始時概述我們的發展計劃的主要成就以及我們的財務表現。

In the second quarter, we achieved key milestones regarding the global regulatory review of our late-stage asset, zanidatamab, including being granted priority review of the Biologics License Application, or BLA, for zanidatamab as second-line treatment for biliary tract cancers, or BTC, in the United States with a target action date of November 29, 2024.

第二季度，我們在對後期資產 zanidatamab 的全球監管審查方面實現了關鍵里程碑，包括獲得對 zanidatamab 作為膽道癌二線治療的生物製品許可證申請（BLA）的優先審查，或BTC，在美國，目標行動日期為2024 年11 月29 日。

Similarly, the European Medicines Agency has validated the Marketing Authorization Application for zanidatamab in second-line BTC, and regulatory reviews for zanidatamab in BTC remain underway in China. We are pleased to have received a milestone payment of USD8 million in July under the terms of Zymeworks Asia Pacific's license and collaboration agreement with BeiGene in conjunction with zanidatamab's BLA acceptance in China.

同樣，歐洲藥品管理局已經驗證了扎尼達單抗在二線BTC的行銷授權申請，扎尼達單抗在BTC的監管審查仍在進行中。我們很高興根據 Zymeworks Asia Pacific 與百濟神州的許可和合作協議條款以及 zanidatamab 在中國獲得 BLA 的接受，於 7 月收到了 800 萬美元的里程碑付款。

Our partner, Jazz, has confirmed that the pivotal HERIZON-GEA-01 trial evaluating zanidatamab in first-line gastroesophageal adenocarcinoma, or GEA, is ongoing and enrollment remains on track. Based on a blinded assessment of progression events, Jazz estimates top-line progression-free survival, or PFS, data will be available in second quarter 2025. Jazz continues to track events in the trial relative to the initial protocol assumptions.

我們的合作夥伴 Jazz 已確認，評估 zanidatamab 治療一線胃食道腺癌 (GEA) 的關鍵 HERIZON-GEA-01 試驗正在進行中，入組工作仍在進行中。根據對進展事件的盲法評估，Jazz 估計頂級無惡化存活期 (PFS) 數據將於 2025 年第二季提供。Jazz 繼續追蹤試驗中與最初協議假設相關的事件。

Near term, we look forward to a potential approval for zanidatamab in second-line BTC in the United States. And based on the expected time line and subject to approval, Jazz is aiming to launch zanidatamab in the United States for second-line BTC in the fourth quarter of 2024. Together with our partners, we look forward to opportunities where we can continue presenting promising data that support deep and durable responses, further highlighting zanidatamab's potential to provide meaningful benefits for patients.

短期內，我們期待 zanidatamab 在美國可能獲得二線 BTC 批准。根據預期時間線並待批准，Jazz 計劃於 2024 年第四季在美國推出二線 BTC 的 zanidatamab。我們與我們的合作夥伴一起期待有機會繼續提供有希望的數據，支持深入而持久的反應，進一步強調扎尼達單抗為患者提供有意義的益處的潛力。

This includes the first-ever overall survival findings from the Phase 2b HERIZON-BTC-01 clinical trial for zanidatamab presented at the American Society of Clinical Oncology Annual Meeting by our partner, Jazz. Results from this long-term analysis of the trial indicate that zanidatamab as monotherapy demonstrated sustained and durable anti-tumor responses in previously treated patients with HER2-positive BTC and support the clinically meaningful benefit of continued treatment with zanidatamab. The safety profile in all enrolled patients remained manageable with favorable tolerability compared with the initial analysis.

這包括我們的合作夥伴 Jazz 在美國臨床腫瘤學會年會上發表的 zanidatamab 2b 期 HERIZON-BTC-01 臨床試驗的首次整體存活結果。該試驗的長期分析結果表明，扎尼達單抗作為單一療法在先前接受過治療的HER2 陽性BTC 患者中表現出持續且持久的抗腫瘤反應，並支持繼續使用扎尼達單抗治療具有臨床意義的益處。與初步分析相比，所有入組患者的安全性仍處於可控範圍內，且具有良好的耐受性。

In addition, we are pleased to report significant progress for our wholly owned pipeline, which transitions two of Zymeworks early-stage programs into clinical candidates. We have successfully cleared IND applications by the FDA for ZW191 and ZW171 with first in-human studies planned to initiate in the second half of 2024 in the United States. And we are actively progressing applications seeking regulatory permission to commence clinical studies for ZW191 and ZW171 in other non-US jurisdictions in the second half of 2024.

此外，我們很高興地報告我們的全資管道取得了重大進展，該管道將 Zymeworks 的兩個早期項目轉變為臨床候選項目。我們已成功批准 FDA 對 ZW191 和 ZW171 的 IND 申請，並計劃於 2024 年下半年在美國啟動首次人體研究。我們正在積極推動申請，尋求監管許可，以便於 2024 年下半年在其他非美國司法管轄區開始 ZW191 和 ZW171 的臨床研究。

With these advancements in mind, following a strategic review of our emerging wholly owned pipeline, we made the decision to formally discontinue the clinical development program of our HER2-targeted antibody-drug conjugate, zanidatamab zovodotin, also known as ZW49 or zani zo. This decision aligns with our commitment to focus on the development of our early-stage programs, which we believe have the potential to be best-in-class and/or first-in-class therapeutics.

考慮到這些進步，在對我們新興的全資管道進行策略性審查後，我們決定正式停止 HER2 標靶抗體藥物綴合物 zanidatamab zovodotin（也稱為 ZW49 或 zani zo）的臨床開發計劃。這項決定符合我們專注於開發早期專案的承諾，我們相信這些專案有潛力成為一流和/或一流的治療方法。

By reallocating our resources, we can focus on accelerating the progression of ZW171 and ZW191 into the dose escalation stage of the respective Phase 1 clinical trials as well as the planned IND filings for ZW220 and ZW251 in 2025. We believe zani zo remains a promising Phase 2-ready asset.

透過重新分配資源，我們可以專注於加速ZW171和ZW191進入各自1期臨床試驗的劑量遞增階段，以及計劃於2025年提交ZW220和ZW251的IND申請。我們相信 zani zo 仍然是一項有前途的第二階段資產。

And we continue to explore partnering discussions where zani zo may provide complementary coverage to a pipeline for non-small cell lung cancer, breast cancer, and other indications. Our team extends heartfelt gratitude to the patients, families, and healthcare professionals involved in the zani zo development program.

我們將繼續探索合作討論，zani zo 可能為非小細胞肺癌、乳癌和其他適應症的管道提供補充覆蓋。我們的團隊向參與 zani zo 發展計畫的患者、家屬和醫療保健專業人員表示衷心的感謝。

We remain committed to the highest degree of scientific rigor in our development processes with the goal of focusing on candidates with the potential to deliver the greatest benefit to patients. Our broader oncology development program continues to be a priority with two Phase 1 trials anticipated to commence in 2024, including enrollment of patients with non-small cell lung cancer.

我們仍然致力於在開發過程中保持最高程度的科學嚴謹，目標是專注於有潛力為患者帶來最大利益的候選人。我們更廣泛的腫瘤學開發計畫仍然是優先事項，兩項 1 期試驗預計將於 2024 年開始，包括招募非小細胞肺癌患者。

Turning to our financial position. This afternoon, Zymeworks reported financial results for the second quarter of year 2024. Zymeworks' net loss for the six months ended June 30, 2024, was $69.3 million, or $0.91 loss per diluted share, compared to a net loss of $75.5 million for the same period in 2023. The decrease in net loss was primarily due to lower research and development and general and administrative expenses, which was partially offset by a decrease in revenue and an impairment charge recognized in 2024 related to zanidatamab zovodotin.

轉向我們的財務狀況。今天下午，Zymeworks 公佈了 2024 年第二季的財務表現。截至 2024 年 6 月 30 日的六個月，Zymeworks 的淨虧損為 6,930 萬美元，或稀釋後每股虧損 0.91 美元，而 2023 年同期的淨虧損為 7,550 萬美元。淨虧損減少主要是由於研發以及一般和管理費用減少，但部分被收入減少和 2024 年確認的與扎尼達塔瑪布佐沃多汀相關的減值費用所抵消。

As reported, our revenue for the six months ended June 30, 2024, was $29.3 million compared to $42.6 million for the same period in 2023. Revenue for the six months ended June 30, 2024, included $20.7 million for development support and drug supply revenue from Jazz, $8 million of milestone revenue from BeiGene in relation to the acceptance by the CDE of the NMPA in China of the BLA for zanidatamab for second-line treatment of HER2-positive BTC, $0.4 million from BeiGene for research support payments, and $0.2 million from our partners for research support and other payments.

據報道，截至 2024 年 6 月 30 日的六個月，我們的收入為 2,930 萬美元，而 2023 年同期為 4,260 萬美元。截至2024 年6 月30 日止六個月的收入包括來自Jazz 的2070 萬美元的開發支持和藥品供應收入，以及百濟神州因中國NMPA 的CDE 接受扎尼達他單抗的BLA 而獲得的800萬美元的里程碑收入。

Revenue for the same period in 2023 included $61 million for development support and drug supply revenue from Jazz, which was partially offset by a $20.1 million credit issued to Jazz for contractual amendments to our partnership arrangement and $1.7 million from our partners for research support and other payments.

2023 年同期的收入包括來自Jazz 的6,100 萬美元的開發支援和藥品供應收入，這部分被向Jazz 發放的2,010 萬美元信用額度（用於修改我們的合作夥伴關係安排的合約）以及來自合作夥伴的170 萬美元的研究支持和其他收入所部分抵消。

Overall, operating expenses were $110 million for the six months ended June 30, 2024, compared to $124 million for the same period in 2023, representing a decrease of 11% year over year. The decrease in overall operating expenses resulted from a decrease in both research and development expense as well as a decrease in general and administrative expense.

整體而言，截至2024年6月30日的六個月營運費用為1.1億美元，而2023年同期營運費用為1.24億美元，年減11%。整體營運費用的減少是由於研發費用以及一般和管理費用的減少。

The decrease in research and development expense was primarily due to a decrease in expenses for zanidatamab as a result of transfer of responsibility for this program to Jazz. This decrease, compared to the same period in 2023, was partially offset by an increase in expenses of other development programs, primarily with respect to product candidates ZW171 and ZW251, costs incurred for manufacturing activities to support the IND for ZW220, and other preclinical and research programs.

研發費用的減少主要是由於該專案的責任轉移給 Jazz，導致 zanidatamab 的費用減少。與 2023 年同期相比，這一下降被其他開發項目費用的增加部分抵消，主要涉及候選產品 ZW171 和 ZW251、支持 ZW220 IND 的製造活動以及其他臨床前和研究計劃。

Salaries and benefits expenses decreased compared to the same period in 2023 due to non-recurring severance expenses in 2023, which was partially offset by an increase in stock-based compensation expense in 2024. The decrease in general and administrative expense was primarily due to a decrease in external consulting expenses for information technology, legal fees, and other expenses for advisory services; a reduction in insurance costs; and a decrease in depreciation and amortization expenses compared to the same period in 2023.

由於2023年的非經常性遣散費，薪資和福利費用較2023年同期有所下降，但部分被2024年股票薪酬費用的增加所抵銷。一般及管理費用減少主要是因為資訊科技外部諮詢費用、法律費用以及其他諮詢服務費用減少；保險費用減少；與2023年同期相比，折舊和攤提費用減少。

This was partially offset by costs due to the termination of our long-term facility lease in Seattle in 2024. During the six months ended June 30, 2024, we recorded a non-cash impairment charge of $17.3 million as a result of the company's decision to discontinue the zanidatamab zovodotin clinical development program, which utilize the technology represented by acquired in-process research and development assets.

這部分被我們於 2024 年終止西雅圖長期設施租約所產生的成本所抵銷。截至2024 年6 月30 日的六個月內，由於公司決定終止zanidatamab zovodotin 臨床開發項目，我們記錄了1730 萬美元的非現金減值費用，該項目利用了所收購的正在進行的研發所代表的技術資產。

As of July 31, 2024, we had approximately 71 million shares of common stock outstanding and approximately 5.1 million shares of common stock issuable under prefunded warrants. As of June 30, 2024, we had $395.9 million of cash resources, consisting of cash, cash equivalents, and marketable securities, as compared to $456.3 million as of December 31, 2023.

截至 2024 年 7 月 31 日，我們擁有約 7,100 萬股已發行普通股及約 510 萬股可依預融資認股權證發行的普通股。截至 2024 年 6 月 30 日，我們擁有 3.959 億美元的現金資源，包括現金、現金等價物和有價證券，而截至 2023 年 12 月 31 日，我們的現金資源為 4.563 億美元。

For additional details on our quarterly and year-end results, I encourage you to review our earnings release and other SEC filings as available on our website at www.zymeworks.com. Our strategy of refocusing the business and building a diverse clinical-stage product pipeline of antibody-drug conjugates or ADCs and multispecific antibody therapeutics continues to provide a solid foundation, which we believe will help to achieve our long-term goal of identifying additional product candidates and seeking valuable partnership options where appropriate to assist in global development and commercialization.

有關我們季度和年終業績的更多詳細信息，我鼓勵您查看我們的收益報告和其他 SEC 文件，這些文件可在我們的網站 www.zymeworks.com 上找到。我們重新調整業務重點並建立抗體藥物偶聯物或ADC 和多特異性抗體療法的多樣化臨床階段產品線的策略繼續提供堅實的基礎，我們相信這將有助於實現我們確定其他候選產品的長期目標並在適當的情況下尋求有價值的合作夥伴選擇，以協助全球開發和商業化。

Based on current operating plans, our strong financial position of $395.9 million in cash resources as of June 30, 2024, together with certain anticipated regulatory milestone payments gives us an expected runway into the second half of 2027. We may also be able to extend this runway or fund an expanded R&D scope through potential regulatory approval milestone payments in connection with our existing partnerships with Jazz and BeiGene or new partnerships and collaborations, which we may choose to form.

根據目前的營運計劃，截至 2024 年 6 月 30 日，我們擁有 3.959 億美元的現金資源，加上某些預期的監管里程碑付款，為我們提供了進入 2027 年下半年的預期跑道。我們還可以透過與 Jazz 和百濟神州的現有合作夥伴關係或我們可能選擇建立的新夥伴關係和合作相關的潛在監管批准里程碑付款來擴展這條跑道或資助擴大的研發範圍。

In addition, pending regulatory approval, we are eligible to receive commercial milestone payments based on annual sales of zanidatamab and tiered royalties between 10% and 20% on Jazz's annual net sales and between 10% and 19.5% on BeiGene's net sales.

此外，在等待監管部門批准的過程中，我們有資格獲得基於扎尼達他單抗年銷售額的商業里程碑付款以及Jazz 年淨銷售額10% 至20% 和百濟神州淨銷售額10% 至19.5% 之間的分級特許權使用費。

With that, I'd like to hand over to our Chief Scientific Officer, Dr. Paul Moore, who will provide more details regarding our wholly owned pipeline and specifically on ZW191 and ZW171 moving into the clinic. Over to you, Paul.

接下來，我想將工作交給我們的首席科學官 Paul Moore 博士，他將提供有關我們全資管道的更多詳細信息，特別是有關 ZW191 和 ZW171 進入臨床的信息。交給你了，保羅。

Thank you, Bijal. So today, I'm delighted to be talking about our growing oncology pipeline, which is currently built on two fundamental pillars, modality focus and therapeutic area focus.

謝謝你，比賈爾。因此，今天，我很高興談論我們不斷增長的腫瘤學管道，目前建立在兩個基本支柱之上：模式重點和治療領域重點。

To date, we have targeted three areas of high unmet medical need, gynecological cancers, lung cancer, and cancers of the digestive system, while balancing ADC and T cell engagers across these various therapeutic areas. We believe this approach ensures both the broad and comprehensive coverage of these challenging diseases.

迄今為止，我們已針對三個醫療需求未被滿足的領域：婦科癌症、肺癌和消化系統癌症，同時在這些不同的治療領域中平衡 ADC 和 T 細胞參與者。我們相信這種方法確保了這些具有挑戰性的疾病的廣泛和全面的覆蓋。

Moving forward, as we continue to progress with the development of our early-stage assets, we believe that expanding on both our modality and therapeutic areas of focus will be key in driving the growth of our pipeline in the coming months and years. This includes leveraging our deep technical expertise to combine and adapt various modalities with the aim to improve patient outcome. You will hear more about that on our plans for growth and expansion later in the year, including the nomination of our fifth product candidate, a trispecific T cell engager, or TriTCE.

展望未來，隨著我們繼續推動早期資產的開發，我們相信擴大我們的模式和治療重點領域將是未來幾個月和幾年推動我們的產品線成長的關鍵。這包括利用我們深厚的技術專業知識來結合和調整各種模式，以改善患者的治療效果。您將在今年稍後聽到有關我們成長和擴張計劃的更多信息，包括提名我們的第五種候選產品、三特異性 T 細胞接合劑或 TriTCE。

Our strategic balance of wholly owned ADCs and T cell engagers targeting clinically validated antigens like folate receptor alpha, NaPi2b, and mesothelin underscores our commitment to deliver innovative treatments that meet the highest standards of care not only as monotherapy, but also in combination with agents that have already shown previous activity and benefit.

我們針對葉酸受體α、NaPi2b 和間皮素等臨床驗證抗原的全資ADC 和T 細胞接合劑的戰略平衡強調了我們致力於提供滿足最高護理標準的創新治療方法，不僅作為單一療法，而且還與以下藥物合併使用：已顯示出先前的活動和益處。

ZW171 and ZW191 are both designed to optimize efficacy, starting with the selection of targets with the highest level of expression. As you can see here, across ovarian cancer, mesothelin, folate receptor, and NaPi2b are expressed at relatively higher levels compared to other targets such as cadherin-6, providing a broad and comprehensive coverage of ovarian cancer, something which also holds in non-small cell lung cancer.

ZW171 和 ZW191 均旨在優化功效，首先選擇具有最高表達量的標靶。正如您在此處所看到的，在卵巢癌中，與鈣粘蛋白6 等其他標靶相比，間皮素、葉酸受體和NaPi2b 的表達水平相對較高，從而提供了廣泛而全面的卵巢癌覆蓋範圍，這在非卵巢癌中也是如此。

We believe that the relatively high tumor expression levels are crucial for maximizing the efficacy of our therapeutic agents, helping the ADCs and T cell engagers to effectively bind to and eliminate cancer cells regardless of modality. By leveraging T cell killing through an enhanced two-plus-one format in unique geometry, our ZW171 candidate offers a potentially robust and precise immune response against mesothelin-expressing tumors and helps to enhance our position in the competitive landscape.

我們相信，相對較高的腫瘤表達水平對於最大化我們的治療藥物的功效至關重要，幫助 ADC 和 T 細胞接合劑有效結合併消除癌細胞，無論採用何種方式。透過以獨特的幾何形狀增強的二加一格式利用T 細胞殺傷，我們的ZW171 候選藥物提供了針對錶達間皮素的腫瘤的潛在強大而精確的免疫反應，並有助於增強我們在競爭格局中的地位。

Similarly, leveraging a unique antibody payload linker for ZW191 offers a potential robust and effective therapy against folate receptor alpha-expressing tumors. This quarter, we have achieved significant milestones in progressing our pipeline by advancing both ZW171 and ZW191 into clinical stage development.

同樣，利用 ZW191 的獨特抗體有效負載連接器為表達葉酸受體 α 的腫瘤提供了一種潛在的穩健且有效的療法。本季度，我們透過將 ZW171 和 ZW191 推進到臨床階段開發，在研發管線方面取得了重要的里程碑。

With the FDA clearance of these INDs, we are one step closer to our goal of providing patients with potentially best-in-class therapeutics that could improve the standard of care for these treatment landscapes. T cell engagers offer great opportunity for more effective therapies. And in particular, ZW171 has the potential to keep patients with the right range of tumors with moderate to strong mesothelin expression observed in ovarian cancer, pancreatic cancer, non-small cell lung cancer, and endometrial cancer.

隨著 FDA 對這些 IND 的批准，我們距離為患者提供潛在的一流療法以提高這些治療領域的護理標準的目標又近了一步。T 細胞參與者為更有效的治療提供了絕佳的機會。特別是，ZW171 有潛力保留在卵巢癌、胰腺癌、非小細胞肺癌和子宮內膜癌中觀察到的中度至強間皮素表達的正常腫瘤範圍的患者。

However, the opportunity for developing T cell engager targeting mesothelin-expressing cancers doesn't come without its challenges. For ZW171, we have taken a thoughtful approach to what a target profile would look like for this patient population. And we believe in our design approach, which uses an avidity-dependent mesothelin binding of two mesothelin paratopes to enable selective cystic tumor cells with high mesothelin expression relative to normal tissues and reduces the impact of soluble mesothelin and potency, potentially minimizing -- potentially minimizes off tumor on target toxicity.

然而，開發針對錶達間皮素的癌症的 T 細胞接合劑的機會並非沒有挑戰。對於 ZW171，我們採取了深思熟慮的方法來確定該患者群體的目標概況。我們相信我們的設計方法，它使用兩個間皮素互補位的親和力依賴性間皮素結合，使選擇性囊性腫瘤細胞相對於正常組織具有高間皮素表達，並減少可溶性間皮素和效力的影響，潛在地最小化－潛在地最小化遠離腫瘤的目標毒性。

On slide 13, the preclinical data shown here demonstrates ZW171's ability to exhibit mesothelin-dependent cytotoxicity across various cancer cell lines, including lung, ovarian, colorectal, and mesothelioma. In cancer cell lines with relatively high or moderate mesothelin expression, including representative lung and ovarian cancer, CRC, and mesothelial lung cancer cell lines, ZW171 demonstrates potent cytotoxic effects, significantly reducing tumor cell survival at low concentrations.

在幻燈片 13 上，此處顯示的臨床前數據證明了 ZW171 在各種癌細胞系（包括肺癌、卵巢癌、結直腸癌和間皮瘤）中表現出間皮素依賴性細胞毒性的能力。在間皮素表達相對較高或中等的癌細胞系中，包括代表性的肺癌和卵巢癌、大腸直腸癌和間皮肺癌細胞系，ZW171表現出有效的細胞毒性作用，在低濃度下可顯著降低腫瘤細胞的存活率。

Importantly, in cell lines with relatively low mesothelin expression relative -- reflective of mesothelin expression on normal healthy tissue, ZW171 showed minimal cytotoxic effects similar to the negative control. We believe that this selective activity helps to ensure that ZW171 specifically targets mesothelin-expressing tumor cells, minimizing potential off-target effects and improving safety profiles. The demonstrated efficacy across high and moderate mesothelin-expressing tumors suggests a broad therapeutic potential for ZW171, including various cancers as shown in the previous slide.

重要的是，在間皮素表達相對較低的細胞系中（反映了正常健康組織上的間皮素表達），ZW171 顯示出與陰性對照相似的最小細胞毒性作用。我們相信，這種選擇性活性有助於確保 ZW171 特異性靶向表達間皮素的腫瘤細胞，最大限度地減少潛在的脫靶效應並提高安全性。在高和中度間皮素表達腫瘤中所表現出的功效表明 ZW171 具有廣泛的治療潛力，包括上一張幻燈片中所示的各種癌症。

Based on these promising preclinical results, we are preparing to further validate these findings in a clinical setting. We expect to dose first patient this year in our Phase 1, open-label, multicenter study of ZW171 in participants with advanced or metastatic ovarian cancer, non-small cell lung cancer, and other mesothelin-expressing cancers.

基於這些有希望的臨床前結果，我們準備在臨床環境中進一步驗證這些發現。我們預計今年將在 ZW171 的 1 期、開放標籤、多中心研究中對患有晚期或轉移性卵巢癌、非小細胞肺癌和其他表達間皮素的癌症的受試者進行首例患者給藥。

The Phase 1 study design is now available on clinicaltrials.gov website under the NCT number 06523803. The global study is expected to enroll 160 participants across North America, Europe, and Asia Pacific regions.

第一期研究設計現已在 ClinicalTrials.gov 網站上發布，NCT 編號為 06523803。這項全球研究預計將招募來自北美、歐洲和亞太地區的 160 名參與者。

Part 1 of the study will evaluate the safety and tolerability of ZW171, and Part 2 of the study will evaluate the antitumor activity of ZW171 according to the RECIST evaluation criteria while continuing to evaluate the safety and tolerability. Inclusion criteria includes pathologically confirmed diagnosis of cancers with evidence of locally advanced, unresectable, and/or metastatic disease; cancers that are refractory to all available standard of care treatment; cancers for which no standard of care treatment is available while the participant cannot tolerate or refuses standard of care therapy. We look forward to reporting first patient dose in the near future and discussing progress in the coming earning calls.

研究第1部分將評估ZW171的安全性和耐受性，研究第2部分將根據RECIST評估標準評估ZW171的抗腫瘤活性，同時持續評估安全性和耐受性。納入標準包括經病理學證實的癌症診斷，並有局部晚期、不可切除和/或轉移性疾病的證據；所有現有標準護理治療都難以治癒的癌症；沒有標準護理治療且參與者不能耐受或拒絕標準護理治療的癌症。我們期待在不久的將來報告第一例病患劑量，並在即將到來的財報電話會議中討論進展。

Now moving to ZW191, which highlights our continued focus on targeting antigens with high levels of expression as I described earlier. As illustrated in the attached slide, folate receptor alpha is frequently overexpressed in a substantial portion of non-small cell lung cancer, ovarian cancer, and endometrial cancer.

現在轉向 ZW191，它凸顯了我們對高表達水平抗原的持續關注，正如我之前所述。如所附幻燈片所示，葉酸受體α在大部分非小細胞肺癌、卵巢癌和子宮內膜癌中經常過度表達。

In non-small cell lung cancer -- non-small cell lung cancer, adenocarcinoma, for example, over 70% of patients have been reported to exhibit folate receptor alpha positivity with significant portions demonstrating high expression levels as defined by TPS over 50% and IHC score of greater than or equal to 2-plus.

在非小細胞肺癌中，例如非小細胞肺癌、腺癌，據報道，超過 70% 的患者表現出葉酸受體 α 陽性，其中顯著部分錶現出高表達水平，如 TPS 定義的超過 50% 和IHC 評分大於或等於2+。

Similarly, in ovarian cancer, around 80% of platinum-resistant ovarian cancer tumors express some level of folate receptor alpha with 35% scoring is folate receptor alpha high. Endometrial cancer also represent -- presents a notable opportunity with 33% of tumor scoring that's folate receptor alpha positive and 15% that's folate receptor alpha high.

同樣，在卵巢癌中，約 80% 的鉑耐藥性卵巢癌腫瘤表達一定水平的葉酸受體 α，其中 35% 的葉酸受體 α 評分較高。子宮內膜癌也代表一個顯著的機會，33% 的腫瘤評分為葉酸受體 α 陽性，15% 的腫瘤評分為葉酸受體 α 高。

By focusing on antigens such as folate receptor alpha, which are commonly expressed in these cancers, we aim to develop treatments that not only demonstrate strong therapeutic efficacy but also minimize off-target effects, potentially improving patient outcomes. We are pleased to report that the FDA has cleared IND submission for ZW191.

透過關注這些癌症中常見的葉酸受體α等抗原，我們的目標是開發出不僅具有強大的治療功效，還能最大限度地減少脫靶效應的治療方法，從而有可能改善患者的治療結果。我們很高興地報告 FDA 已批准 ZW191 的 IND 提交。

We're working -- we're looking forward to seeing how our unique design and novel payload for this ADC translates in a clinical setting. As we have discussed previously on these calls, our efforts on developing a novel topoisomerase 1 inhibitor, or TOPO1i payload known as ZD06519 ,has focused on selecting properties that we expect would drive strong efficacy while maximizing tolerability, specifically moderate potency with high bystander activity.

我們正在努力——我們期待看到我們針對該 ADC 的獨特設計和新穎的有效負載如何在臨床環境中轉化。正如我們先前在這些電話會議中所討論的，我們在開發一種新型拓樸異構酶1 抑制劑或稱為ZD06519 的TOPO1i 有效負載方面所做的努力重點是選擇我們期望能夠帶來強大功效的特性，同時最大限度地提高耐受性，特別是中等效力和高旁觀者活性。

ZD06519 was designed and selected to potentially allow high antibody dose in humans compared to ADCs with more potent TOPO1 inhibitor payloads, as evidenced by the DXd ADCs. In non-human primate studies, we observed superior tolerability of the 519 ADCs as exemplified at the 120 mg per kg dose of ADCs with a drug antibody ratio of 4. We then implemented well-established and clinically validated linker and antibody attachment chemistry with a balanced approach of designed instability.

與具有更有效 TOPO1 抑制劑有效負載的 ADC 相比，ZD06519 的設計和選擇可能允許在人體中使用高抗體劑量，正如 DXd ADC 所證明的那樣。在非人靈長類動物研究中，我們觀察到 519 種 ADC 具有優異的耐受性，例如 ADC 劑量為 120 mg/kg，藥物抗體比為 4。然後，我們採用了設計不穩定性的平衡方法，實施了完善且經過臨床驗證的接頭和抗體附著化學。

As you can see here in the bottom section of the table, ADCs with higher stability show an unexpected or higher toxicity compared to the DXd platform. On slide 17, as we highlighted in our AACR poster presentations earlier this year, we demonstrate the relative internalization by ZW191's folate receptor alpha monoclonal antibody compared to folate receptor alpha targeting antibodies [encompassing four] other ADC programs.

正如您在表格底部看到的，與 DXd 平台相比，具有更高穩定性的 ADC 顯示出意想不到的或更高的毒性。在幻燈片17 上，正如我們在今年早些時候的AACR 海報演示中所強調的那樣，我們展示了ZW191 葉酸受體α 單克隆抗體與葉酸受體α 靶向抗體（包括四種）其他ADC 項目相比的相對內化作用。

As you can see, ZW191's monoclonal antibody in dark blue demonstrated higher levels of internalization compared to the monoclonal antibodies from Elahere, MORAb-202, STRO-002, and PRO1184. This observation is consistent with our decision to select the ZW191 monoclonal antibody from a larger pool of antibodies for its ability to deliver payload through enhanced internalization and our care in factoring in all components of the ADC when designing our candidates.

如您所見，與 Elahere、MORAb-202、STRO-002 和 PRO1184 的單株抗體相比，ZW191 的深藍色單株抗體表現出更高水平的內化。這項觀察結果與我們從更大的抗體庫中選擇ZW191 單株抗體的決定是一致的，因為它能夠透過增強的內化來提供有效負載，並且我們在設計候選藥物時仔細考慮了ADC 的所有組件。

This type of spheroid model is more predictive of antitumor activity in, in vivo models than traditional [two T cell line] models and also aids in the dissection of ADC mechanism of action, which gives us confidence in being able to replicate these results in humans. Further, for ZW191, we are pleased to have achieved the highest non-severely toxic dose in non-human primates of 60 mg per kg, presenting a compelling profile for potential efficacious dosing in our Phase 1 clinical trial expected to initiate later this year.

這種類型的球體模型比傳統的[兩種 T 細胞系]模型更能預測體內模型的抗腫瘤活性，也有助於剖析 ADC 的作用機制，這使我們有信心在人類身上複製這些結果。此外，對於ZW191，我們很高興在非人靈長類動物中達到了最高的非嚴重毒性劑量，即每公斤60 毫克，這為我們預計將於今年晚些時候啟動的1 期臨床試驗中的潛在有效劑量提供了令人信服的資料。

I will now hand over to Ken, our CEO and Chair, for closing remarks before we begin the Q&A portion of the call.

現在，在我們開始電話會議的問答部分之前，我將請我們的執行長兼主席 Ken 發表結束語。

That's great. Thank you, Paul. We're excited to see how our data-driven approach for designing and developing both ZW171 and ZW191 translates into our respective Phase 1 studies. And we remain dedicated to advancing transformative therapies with IND submissions for ZW220 and ZW251 in 2025, as well as nominating our TriTCE product candidate later this year.

那太棒了。謝謝你，保羅。我們很高興看到我們用於設計和開發 ZW171 和 ZW191 的數據驅動方法如何轉化為我們各自的一期研究。我們仍然致力於在 2025 年提交 ZW220 和 ZW251 的 IND 申請，推進變革性療法，並在今年稍後提名我們的 TriTCE 產品候選者。

On another business update, we're pleased to announce the appointment of Leone Patterson as Executive Vice President, Chief Business Officer, and Chief Financial Officer, effective September 1. Ms. Patterson brings more than 20 years of public company biotech experience with a proven track record of guiding strategy, finance, operations and government through multiple phases of growth. Leone's expertise in planning and executing successful financial strategies will be key as we continue to plan for the next period of growth and expansion for the company.

在另一項業務更新中，我們很高興地宣布任命 Leone Patterson 為執行副總裁、首席商務官兼首席財務官，該任命於 9 月 1 日生效。Patterson 女士擁有 20 多年的上市生物技術經驗，在多個發展階段指導策略、財務、營運和政府方面擁有良好的記錄。當我們繼續規劃公司下一階段的成長和擴張時，Leone 在規劃和執行成功財務策略方面的專業知識將發揮關鍵作用。

We're pleased to announce that our partner, Jazz, has initiated the Phase 3 EmpowHER trial, which is designed to evaluate zanidatamab in combination with chemotherapy after progression on an HER2, where there's an opportunity for zanidatamab to be the first HER2-targeted therapy to demonstrate efficacy and safety in breast cancer patients after an HER2 treatment.

我們很高興地宣布，我們的合作夥伴 Jazz 已啟動 3 期 EmpowHER 試驗，該試驗旨在評估 HER2 進展後的 zanidatamab 與化療的聯合治療，其中 zanidatamab 有機會成為第一個 HER2 靶向療法證明乳腺癌患者接受HER2 治療後的有效性和安全性。

Together with our partners, Jazz and BeiGene, we look forward to sharing more data on zanidatamab's efficacy this year during peer-reviewed medical meetings where we can further validate zanidatamab's potential to improve the standard of care for these patients. We're also looking forward to the pivotal Phase 3 readout -- top-line data readout in our first-line GEA study by our partner, Jazz, who estimate top line PFS data will be available in the second quarter of 2025.

我們期待與我們的合作夥伴 Jazz 和百濟神州一起，在今年的同行評審醫學會議上分享更多有關 zanidatamab 療效的數據，以便進一步驗證 zanidatamab 提高這些患者護理標準的潛力。我們也期待關鍵的第 3 階段讀數——我們的合作夥伴 Jazz 在我們的一線 GEA 研究中讀出的頂線數據，他們估計頂線 PFS 數據將於 2025 年第二季度提供。

In the near term, we also look forward to an important catalyst, our upcoming PDUFA date of November 29, 2024, for our zanidatamab filing in second-line BTC in the United States.

短期內，我們也期待一個重要的催化劑，即將到來的 PDUFA 日期（2024 年 11 月 29 日），用於我們在美國二線 BTC 的 zanidatamab 申請。

Before we turn the call over to Q&A, I'd like to talk about the share repurchase program, which was announced via a press release concurrent with our second-quarter 2024 financial report. As disclosed in the press release, our Board has authorized a $60 million share repurchase program with $30 million of the program repurchases expected to begin promptly and continue during the second half of 2024.

在我們將電話轉入問答之前，我想談談股票回購計劃，該計劃是透過與 2024 年第二季財務報告同時發布的新聞稿宣布的。正如新聞稿中所披露的，我們的董事會已批准一項 6000 萬美元的股票回購計劃，其中 3000 萬美元的回購計劃預計將立即開始，並在 2024 年下半年繼續進行。

This decision reflects our confidence in the future outlook for our business, the potential of our product candidate portfolio, and the long-term value of our preclinical and clinical development pipeline. We believe our strong capital position, bolstered by our strategic partnerships, enables us to execute on the share repurchase program while maintaining ample cash resources to continue advancing our product candidates portfolio and providing optionality around strategic capital allocation.

這項決定反映了我們對業務未來前景、候選產品組合的潛力以及臨床前和臨床開發管道的長期價值的信心。我們相信，在戰略合作夥伴關係的支持下，我們強大的資本狀況使我們能夠執行股票回購計劃，同時保持充足的現金資源，以繼續推進我們的產品候選組合，並提供圍繞戰略資本配置的選擇性。

The share purchase program is further supported by our decision to deprioritize the development of zani zo, which allows us to reallocate that associated R&D spending. We also expect to maintain our projected cash runway in the second half 2027, assuming completion of the full $60 million share purchase program based on existing cash resources and assuming the receipt of certain anticipated regulatory milestone payments.

我們決定取消 zani zo 的開發優先級，這進一步支持了股票購買計劃，這使我們能夠重新分配相關的研發支出。我們還預計在 2027 年下半年維持預計的現金跑道，假設根據現有現金資源完成全部 6000 萬美元的股票購買計劃，並假設收到某些預期的監管里程碑付款。

We believe our stock is currently undervalued and see this buyback as a strategic way to invest in ourselves through thoughtful capital allocation ahead of upcoming expected catalysts in 2024 and 2025. Our plan to execute the share repurchase in two phases gives us the flexibility to manage repurchases over time, allowing us to adapt to market conditions and pursue additional growth opportunities as they may arise.

我們認為我們的股票目前被低估，並將此次回購視為在 2024 年和 2025 年即將到來的預期催化劑出現之前透過深思熟慮的資本配置進行投資的策略方式。我們計劃分兩個階段執行股票回購，這使我們能夠靈活地管理回購，使我們能夠適應市場條件並在可能出現的情況下尋求額外的成長機會。

By reserving the remaining $30 million for future repurchases, we maintain flexibility that can enable us to capitalize on strategic opportunities without compromising our cash resources. This balanced approach and thoughtful capital allocation enables us to make prudent decisions that we believe will benefit our shareholders both now and in the future.

透過保留剩餘的 3000 萬美元用於未來回購，我們保持了靈活性，使我們能夠在不損害現金資源的情況下利用戰略機會。這種平衡的方法和深思熟慮的資本配置使我們能夠做出審慎的決策，我們相信這些決策將使我們的股東現在和未來受益。

With that, I'd like to thank everyone for listening. And I'll turn the call over to the operator to begin the question-and-answer session. Operator?

在此，我要感謝大家的聆聽。我會將電話轉給接線生開始問答環節。操作員？

(Operator Instructions) Stephen Willey, Stifel.

（操作員說明）Stephen Willey，Stifel。

Yeah. Good afternoon. Thanks for taking questions and thanks for getting ZW171, ZW191 on the clinic. I was just wondering if you can speak to the levels of mesothelin and folate receptor alpha expression that you're requiring at baseline for the Phase 1. What are the IHC cutoff values that you're requiring for both? And then is there anything that you might be able to say about the starting ZW171 dose, the cadence of any step up dosing you'll be using, and any requirements for inpatient administration?

是的。午安.感謝您提出問題，也感謝您在診所購買 ZW171、ZW191。我只是想知道您是否可以談談您在第一階段基線時所需的間皮素和葉酸受體α表達水平。您需要的兩者的 IHC 截止值是多少？那麼，您對 ZW171 的起始劑量、您將使用的任何逐步給藥的節奏以及住院給藥的任何要求有什麼可以說的嗎？

Sure. Thank you, Stephen. Maybe I'll ask Pranshul, who is the Global Clinical Lead for ZW171, if he wants to answer some, but maybe not all of those questions. Stephen?

當然。謝謝你，史蒂芬。也許我會問 ZW171 全球臨床負責人 Pranshul，他是否想回答一些問題，但也許不是全部。史蒂芬？

Stephen, thank you for your question. I can share with you what's publicly available on clinicaltrials.gov. To start off, I think you asked about the expression levels of mesothelin and folate receptor alpha in our studies. Initially, in our dose escalation phases, we'll be analyzing expression levels retrospectively. So there's no cutoff as such, as some of these are yet to be validated for mesothelin, for example.

史蒂芬，謝謝你的問題。我可以與您分享 ClinicalTrials.gov 上公開的內容。首先，我認為您詢問了我們研究中間皮素和葉酸受體α的表達量。最初，在劑量遞增階段，我們將回顧性分析表現量。因此，不存在這樣的界限，因為其中一些尚未針對間皮素進行驗證。

Your second question regarding dosing strategy, this is something that we haven't made available publicly yet. However, we do intend to explore various dosing formats of ZW171 in clinic. And your -- what was your next and last piece of the question, Stephen? Sorry.

關於劑量策略的第二個問題，我們尚未公開。然而，我們確實打算在臨床上探索 ZW171 的各種給藥方式。史蒂芬，你的下一個也是最後一個問題是什麼？對不起。

Just a question of any starting dose, step up-dosing, and then any inpatient administration requirements.

只是起始劑量、逐步增加劑量、住院給藥要求的問題。

Yeah. The starting dose is something we haven't shared publicly yet. There will be requirement for inpatient in a small subset of patients during the dose escalation phase, as this is mandated by regulatory requirements in our discussion with the regulatory bodies. However, we do intend to work at different strategies for dosing where we will explore dosing with hospitalization requirements later on in the study.

是的。我們尚未公開分享起始劑量。在劑量遞增階段，一小部分患者將需要住院治療，因為這是我們與監管機構討論中監管要求所規定的。然而，我們確實打算採用不同的劑量策略，我們將在稍後的研究中探索符合住院要求的劑量。

Okay. Can I just ask a clarification question? So just so that I'm clear on the mesothelin side and I guess maybe even on the folate receptor alpha side. You will be enrolling tumor types that you know to be enriched for expression of each of these target antigens and then you'll be retrospectively looking at expression levels via IHC or is that --

好的。我可以問一個澄清問題嗎？這樣我就可以清楚地了解間皮素方面，我想甚至可能了解葉酸受體α方面。您將招募已知富含每種標靶抗原表達的腫瘤類型，然後您將透過 IHC 回顧性地觀察表達水平，或者是--

Exactly.

確切地。

Okay, okay. Thank you for taking my questions.

好吧，好吧。感謝您回答我的問題。

Thank you. Yigal Nochomovitz, Citi.

謝謝。伊格爾·諾霍莫維茨，花旗銀行。

Hi. This is Amin on for Yigal. Thank you for taking our questions. We had a couple. First, on the ZW220. Given the prior failures in NaPi2b ADCs, what do you think differentiates ZW220 from the previously investigated molecules by Mersana and Genentech?

你好。這是阿明替補伊格爾的比賽。感謝您接受我們的提問。我們有一對。首先是ZW220。鑑於 NaPi2b ADC 先前的失敗，您認為 ZW220 與 Mersana 和 Genentech 先前研究的分子有何不同？

And then the second one. On the general ADC strategy, do you see any risk in using the same payload for your three ADC programs? What gives you confidence about this payload?

然後是第二個。在一般 ADC 策略中，您認為為三個 ADC 程式使用相同的有效負載有任何風險嗎？是什麼讓您對這個有效載荷充滿信心？

No, two great questions. Paul, would you like to answer both of those questions?

不，這是兩個很好的問題。保羅，你想回答這兩個問題嗎？

Sure, sure. So first of all, on our confidence level in ZW220 being successful where other's ADCs against NaPi have failed, I think that really comes down to the design of our ADC, from the antibody selected to the payload.

當然，當然。因此，首先，我們對 ZW220 成功的信心水平，而其他針對 NaPi 的 ADC 卻失敗了，我認為這實際上取決於我們 ADC 的設計，從選擇的抗體到有效負載。

So your second question regards to payload -- but as you may be aware, we spent a lot of time really carefully picking what we believe was the right balance of potency, bystander activity for the total payload. So we feel comfortable in what we've selected from a larger options of payloads to select from there.

所以你的第二個問題是關於有效載荷的——但正如你可能知道的，我們花了很多時間非常仔細地選擇我們認為是總有效載荷的效力、旁觀者活動的正確平衡。因此，我們對從更大的有效載荷選項中選擇的內容感到滿意。

And that, we feel, is very important, that level of potency overall across all our ADCs. And particularly for NaPi, there, we think again the safety profile and the efficacy profile and the use of a TOPO payload, which is not what others have tried before, differentiates our program from previous efforts to target through an ADC approach.

我們認為，我們所有 ADC 的整體效力水準非常重要。特別是對於 NaPi，我們再次認為安全性、功效以及 TOPO 有效負載的使用（這是其他人之前沒有嘗試過的）使我們的計劃與之前透過 ADC 方法瞄準的努力不同。

And then regarding your question about using that across three different targets. We feel all of those three targets could benefit within our disease indication from ADCs with this type of payload. And so our preclinical data supports that.

然後關於您關於在三個不同目標中使用它的問題。我們認為所有這三個目標都可以從具有此類有效負載的 ADC 中受益於我們的疾病適應症。因此我們的臨床前數據支持了這一點。

When we benchmark that against competitor programs or prior programs, both the efficacy profile and the breadth of patients that we can tackle with this payload balance with the antibody really looks very favorable. So that supports our moving forward in the clinic with all three programs.

當我們與競爭對手的專案或先前的專案進行基準測試時，我們可以透過抗體的有效負載平衡來應對的功效概況和患者範圍確實看起來非常有利。因此，這支持我們在所有三個項目的臨床工作中取得進展。

Thanks for that. That's very helpful.

謝謝你。這非常有幫助。

Akash Tewari, Jefferies.

阿卡什·特瓦里，杰弗里斯。

Hi. This is [Divy] on for Akash. Jazz announced yesterday that data from HERIZON-GEA-01 was pushed back from late 2024 to Q2 '25. Does that mean that enrollment is progressing slower than originally anticipated or is it just related to not enough PFS events getting accumulated as prespecified by the interim analysis protocol? And have you disclosed any of the number of events for PFS to be accumulated for the preplanned interim analysis? Thank you.

你好。這是阿卡什的 [Divy]。Jazz 昨天宣布，HERIZON-GEA-01 的數據從 2024 年末推遲到 25 年第二季。這是否意味著註冊進度比最初預期的要慢，或者只是與中期分析方案預先指定的累積 PFS 事件數量不足有關？您是否揭露了為預先規劃的中期分析而累積的 PFS 事件數量？謝謝。

Yeah. And as to your first question, I think Jazz was very clear on their guidance after their earnings call because I did listen to it. And they were very clear that enrollment is on track and the delay in unblinded study was related to getting the required number of events to unblinded study, which is currently targeted now in our estimates being Q2 2025. And the answer to your second question, no, there's no disclosure of the actual number of events.

是的。至於你的第一個問題，我認為 Jazz 在財報電話會議後的指導非常明確，因為我確實聽過。他們非常清楚，註冊工作正在按計劃進行，非盲研究的延遲與獲得非盲研究所需的事件數量有關，目前我們的目標是 2025 年第二季。你的第二個問題的答案是，不，沒有透露事件的實際數量。

Okay, understood. Thank you.

好的，明白了。謝謝。

Yeah. No worries.

是的。不用擔心。

Thank you. Brian Cheng, JPMorgan.

謝謝。布萊恩鄭，摩根大通。

Thanks for taking our question. This is [Sean] on for Brian. So first thing, on ZW171. We saw that the Phase 1 was posted on clinicaltrials.gov. How should we think of the side effect profile based on the target you selected? Just curious if there's any additional preclinical insights that you can share? And how many doses are you evaluating? And I have a quick follow-up.

感謝您提出我們的問題。這是布萊恩的[肖恩]。首先，在 ZW171 上。我們看到第一階段已發佈在 ClinicalTrials.gov 上。我們應該如何根據您選擇的目標來看待副作用？只是好奇您是否可以分享任何其他臨床前見解？您正在評估多少劑量？我有一個快速的跟進。

Paul, do you want to take the first question about preclinical characterization, the tolerability of mesothelin, what we might have seen?

Paul，您想回答關於臨床前特徵、間皮素的耐受性以及我們可能看到的第一個問題嗎？

Yeah, that's a good question, because although -- it is a target that, although it's very highly expressed on cancer types, there is some level of normal expression of mesothelin. And so you have to think carefully about how you differentially target the tumor with avoiding the normal.

是的，這是一個很好的問題，因為儘管它是一個目標，儘管它在癌症類型中表達非常高，但間皮素仍存在一定程度的正常表達。因此，您必須仔細考慮如何區別對待腫瘤並避免正常腫瘤。

And so that's why we spent so much time preclinically trying different formats to get a format that give us that better window, where we wouldn't have activity on low-expressing models that represent normal tissue levels of mesothelin, but that's very potent and doesn't compromise the antitumor activity on the mesothelin-positive tumors, the high-expressing. And that, we've seen in our preclinical profile.

因此，這就是為什麼我們花費大量時間在臨床前嘗試不同的格式，以獲得一種為我們提供更好視窗的格式，在該視窗中，我們不會在代表正常組織間皮素水平的低表達模型上進行活動，但這非常有效，並且不會產生任何影響。我們在臨床前概況中已經看到了這一點。

We've taken the molecules into non-human primates. We've done a lot of other evaluation of the molecules regarding safety. And there, we haven't seen evidence of toxicity.

我們已將這些分子引入非人類靈長類動物體內。我們對分子的安全性進行了許多其他評估。在那裡，我們還沒有看到毒性的證據。

Of course, we have to -- going into the clinic, we'll have to monitor that, pay attention there. That's part of the dosing strategies that Pranshul alluded to that we'll be evaluating. But so far, really we -- we really tried to come up with a design of the modes to address exactly what you're asking.

當然，我們必須——進入診所，我們必須對其進行監控，並注意那裡。這是 Pranshul 提到的我們將要評估的劑量策略的一部分。但到目前為止，我們確實嘗試提出一種模式設計來準確解決您的要求。

And I'll let Pranshul on for the second question about the number of dose levels planned for the Phase 1 study.

我將讓 Pranshul 回答第二個問題，即第一階段研究計劃的劑量水平數量。

Yeah. So we plan to evaluate six different dose levels. This may increase or decrease based on the safety and tolerability profile. DLT evaluation period is 21 days for the study, and -- but we will continue to gather safety and tolerability data as long as the participant remains on trial. And they're to remain on trial if there is toxicity or progression. I hope that answers your question.

是的。因此我們計劃評估六種不同的劑量水平。這可能會根據安全性和耐受性情況而增加或減少。研究的 DLT 評估期為 21 天，但只要參與者仍在試驗中，我們將繼續收集安全性和耐受性數據。如果出現毒性或進展，他們將繼續接受試驗。我希望這能回答你的問題。

And I think you had another question?

我想你還有另一個問題？

Yeah. Thank you for the clarification. I just have a quick modeling question. So we saw that the cash runway hasn't changed. But with zani zo now discontinued, is there any near-term impact that we should model for the R&D expenses? Thank you.

是的。謝謝您的澄清。我只是有一個快速建模問題。所以我們看到現金跑道沒有改變。但隨著 zani zo 現已停產，我們應該為研發費用建模是否有任何近期影響？謝謝。

Yeah. There'll obviously be a subsequent decline in some of the expenses that would have been related to continued spending on zani zo to complete the planned Phase 2 study and prepare for a registration study. So that will decline over the next period of time.

是的。顯然，與繼續在 zani zo 上完成計劃的第二階段研究並準備註冊研究相關的一些費用隨後會下降。因此，在接下來的一段時間內，這一數字將會下降。

And again, that's approximately $30 million that was allocated, which coincidentally matches the initial repurchase program from our share repurchase program. So we would expect that that will be released from future R&D expense, and we'll be using that capital to reallocate to the share repurchase program over time.

同樣，分配的金額約為 3000 萬美元，這恰好與我們股票回購計劃中的初始回購計劃相匹配。因此，我們預計這將從未來的研發費用中釋放出來，隨著時間的推移，我們將利用這些資金重新分配給股票回購計畫。

Thanks for taking our questions.

感謝您回答我們的問題。

You're welcome.

不客氣。

Thank you. Jon Miller, Evercore.

謝謝。喬恩‧米勒，《Evercore》。

Yeah, thank you very much for taking my question. I'll start on the mesothelin program. I know you mentioned you'll be looking at mesothelin expression retrospectively in some of these patients. I guess, what are your expectations for those mesothelin-negative patients?

是的，非常感謝您回答我的問題。我將從間皮素計劃開始。我知道您曾提到您將回顧性地觀察其中一些患者的間皮素表達。我想，您對那些間皮素陰性的患者有何期望？

Presumably, there would be an absence of expected activity there. But does the absence of sufficient antigen -- I know you don't see tox from a cytotoxicity perspective in normal-expressing tissues, but can you drive CRS or T cell exhaustion by circulating T cells if you don't have a good antigen sink to sop up the bispecific to the tumor itself?

據推測，那裡不會有預期的活動。但缺乏足夠的抗原是否會導致這種情況——我知道從細胞毒性的角度來看，在正常表達的組織中你看不到毒素，但是如果你沒有良好的抗原池，你能通過循環T 細胞驅動CRS 或T 細胞耗竭嗎？

And sort of separately, maybe relatedly, you note in the slides that you have potency even in the presence of soluble mesothelin, and I'd love to get a little bit more color on that. Is that driven by the binding mode? Do you not bind soluble mesothelin or is there something else going on that's helping you maintain activity?

單獨地，也許相關的是，您在幻燈片中註意到，即使存在可溶性間皮素，您也具有效力，我希望對此有更多的了解。這是由綁定模式驅動的嗎？您是否沒有結合可溶性間皮素，或者是否有其他因素可以幫助您保持活動？

No, thanks, Jon. Paul, do you want to address both of those questions for mesothelin?

不，謝謝，喬恩。保羅，您想解決關於間皮素的這兩個問題嗎？

Yeah, sure. So maybe on the first question about patients that you wouldn't have a mesothelin target or it would be limited, that is possible. I mean, most of the tumor types that we're going into have some level of mesothelin. So we would probably not think it's possible -- unlikely.

是的，當然。因此，對於關於患者的第一個問題，您可能沒有間皮素靶點或其靶點受到限制，這是可能的。我的意思是，我們要研究的大多數腫瘤類型都含有一定程度的間皮素。所以我們可能不會認為這是可能的——不太可能。

But you're right, it theoretically could happen. And I think then -- but your question about then that then leading to potential deleterious effects through T cell exhaustion or having a negative effect, part of the design consistent with other T cell engagers as well. But we also made sure on ZW171, you don't get T cell activation.

但你是對的，理論上這是可能發生的。我想，但你的問題是，透過 T 細胞耗盡或產生負面影響，導致潛在的有害影響，這也是與其他 T 細胞參與者一致的設計的一部分。但我們也確保在 ZW171 上，您不會活化 T 細胞。

The interaction that we've got with the CD3 is very low affinity. And it's not -- it requires first that you co-engage two binding sites on mesothelin to really set the molecule down on a mesothelin target population. And then you engage the CD3, and then that gives you the activation.

我們與 CD3 的相互作用親和力非常低。事實並非如此──它首先需要你共同接合間皮素上的兩個結合位點，才能真正將分子固定在間皮素目標群體上。然後你接合 CD3，然後就可以啟動。

And that's pretty comprehensively looked at. So I'm not so worried about that being a negative effect. The other part about the soluble mesothelin there, we tested that in vitro. And you basically just combined with mesothelin, and there's a very limited impact on the killing and you can still get to maximum levels of killing.

這是非常全面的研究。所以我不太擔心這會產生負面影響。關於可溶性間皮素的另一部分，我們在體外進行了測試。你基本上只是與間皮素結合，對殺傷的影響非常有限，你仍然可以達到最大的殺傷水平。

And I think again that there is partly this avidity-driven effect that we have. And the fact that to get any impact on activity, you really need to be launched or binding to a cellular surface as opposed to a soluble protein. So that -- happy to share more detail on that with you and discuss it further, Jon, but the data speaks to that and supports that mechanism of action.

我再次認為，我們所擁有的這種熱情驅動效應在某種程度上是存在的。事實上，為了對活性產生任何影響，你確實需要發射或結合到細胞表面，而不是可溶性蛋白質。因此，喬恩，很高興與您分享更多細節並進一步討論，但數據說明了這一點並支持了這種行動機制。

Makes sense. Makes sense. I would love to talk more about the detail there, but maybe not on the Q&A session here. I guess, can I ask a follow-up on the folate receptor alpha program?

有道理。有道理。我很想多談論那裡的細節，但也許不會在這裡的問答環節上。我想，我可以詢問葉酸受體 α 計畫的後續嗎？

One of the things you said in the prepared remarks was that you were specifically looking for a payload that would support a higher antibody dose. And I guess I'm curious why that's intrinsically valuable, given that blocking FR alpha isn't in itself effective. So what's the benefit to giving a higher dose versus a lower dose if aggregate payload toxicity is similar?

您在準備好的評論中所說的一件事是，您正在專門尋找支持更高抗體劑量的有效負載。我想我很好奇為什麼這有內在價值，因為阻斷 FR alpha 本身並不有效。那麼，如果總有效負載毒性相似，給予較高劑量與較低劑量的好處是什麼？

Yeah. Yeah, that's a good question. I think there, partly, the thinking is that the higher the dose that you can get into a patient, the more chance you've actually got of getting the drug to target. So you may be aware that lower doses, you've got just the penetrance through into the tumor. Only 1% to 2% of the antibody actually gets to site.

是的。是的，這是一個好問題。我認為，部分想法是，給患者註射的劑量越高，真正使藥物達到目標的機會就越大。所以您可能會意識到，較低的劑量，您只能滲透到腫瘤中。只有 1% 到 2% 的抗體真正到達位點。

So the higher dose you've got in a patient, the more chance you've got of getting a threshold level of antibody ADC into that tumor. And that also gives me the opportunity to also promote as well. That's why it's so important on the front end of the antibody as well.

因此，給予患者的劑量越高，腫瘤中抗體 ADC 達到閾值水平的機會就越大。這也讓我有機會進行宣傳。這就是為什麼它在抗體的前端也如此重要。

That's why we bring up at this point about us having better internalization, because you also want what does get to the tumor to also internalize very efficiently. So that's where our thinking on the design there is. And by having a more moderate payload or potency similar to DXd, that allows you to get that higher dose into a patient so that you've got that better amount of drug that can then get to tumor.

這就是為什麼我們在這一點上提出我們有更好的內化，因為你也希望到達腫瘤的東西也能非常有效地內化。這就是我們對設計的思考。透過具有與 DXd 類似的更適中的有效負載或效力，您可以將更高的劑量注射到患者體內，這樣您就可以獲得更多的藥物來到達腫瘤。

Makes sense. And then I guess one final one on the share repo. I guess I'm just curious about -- this is a use of capital, given expectations for five-plus programs in the clinic and a very -- obviously, a very active drug discovery effort. Is there really excess capital at this point to return cash to shareholders versus driving value through clinical development?

有道理。然後我猜最後一個是關於股票回購的。我想我只是好奇——這是一種資本的使用，考慮到對臨床上五個以上項目的期望，以及非常——顯然，非常積極的藥物發現工作。目前是否真的存在多餘的資本來向股東返還現金而不是透過臨床開發來推動價值？

No, good question. I think if you look at our current operations now, obviously, ZW171, ZW191 are going very fast and are well funded. ZW220 and ZW251 are on schedule to go into the clinic next year. They're well funded. Beyond that, the fifth indication and what's in Paul's portfolio behind that, which we call [Advanced] right now, is well funded and moving forward.

不，好問題。我認為，如果你看看我們現在的營運情況，顯然，ZW171、ZW191 進展非常快，而且資金充足。ZW220和ZW251計劃於明年進入臨床。他們資金充足。除此之外，第五個跡像以及保羅投資組合中的內容，我們現在稱之為[高級]，資金充足並且正在向前推進。

So we think we're adequately funding all the opportunities we have in front of ourselves and are quite happy with the level of R&D investments. Strategically, we've made the decision to claw back the capital allocation we had for zani zo to complete the Phase 2 and prepare for a registration study for the reasons we outlined. And that happens to provide about $30 million of cash, which doesn't need to be allocated to the remaining portfolio, five-by-five, or Paul's Advanced portfolio.

因此，我們認為我們為擺在自己面前的所有機會提供了充足的資金，並對研發投資水準感到非常滿意。從策略上講，我們決定收回為 zani zo 完成第二階段的資本分配，並出於我們概述的原因準備註冊研究。這恰好提供了大約 3000 萬美元的現金，不需要分配給剩餘的投資組合、五乘五的投資組合或保羅的高級投資組合。

We've looked for a little while about opportunities that might be outside to use for that capital. But I think right now, the most thoughtful capital allocation we can make with our current valuation, the catalyst in front of us, the strength of our cash runway, the optimism we have about the outlook being positive going forward, is to again invest in ourselves, which we think will boost total shareholder return.

我們已經尋找了一些可能在外部使用該資本的機會。但我認為，現在，根據我們目前的估值、我們面前的催化劑、我們現金跑道的實力、我們對未來積極前景的樂觀態度，我們可以做出的最深思熟慮的資本配置是再次投資於我們認為這將提高股東總回報。

And we're certainly convinced that a thoughtful capital allocation process, as with periodic buybacks and a smart R&D strategy, can coexist in a biotech company. And hopefully, that's the way to optimize total shareholder return over the long-term and that's what we're committed to.

我們當然相信，深思熟慮的資本配置流程，如定期回購和明智的研發策略，可以在生技公司中共存。希望這是長期優化股東總回報的方法，也是我們所致力於的。

And we've seen the opportunity now uniquely to do it in front of some catalysts in 2024 and 2025 with some cash that we surely think is excess for now. And therefore, we're going to utilize that in a shareholder program to invest in ourselves. And we think that's of a benefit to all of our shareholders, and so that's what we've chosen to do.

我們現在看到了一個獨特的機會，可以在 2024 年和 2025 年的一些催化劑的推動下，用一些我們認為目前肯定是過剩的現金來實現這一目標。因此，我們將在股東計劃中利用它來投資我們自己。我們認為這對我們所有股東都有好處，因此我們選擇這樣做。

(Operator Instructions) Robert Burns, H.C. Wainwright.

（操作員說明）Robert Burns, H.C.溫賴特。

Congrats (inaudible). [Three] from me, if I may. With regard to ZW171, from a go/no-go signal perspective in the dose escalation, what are you looking to achieve in particular with regards to ovarian cancer and NSCLC? And would what gavo-cel demonstrated in ovarian cancer be a good reference point for us?

恭喜（聽不清楚）。 [三] 來自我，如果可以的話。關於 ZW171，從劑量遞增的通過/不透過訊號角度來看，您特別希望在卵巢癌和非小細胞肺癌方面實現什麼目標？gavo-cel 在卵巢癌中所證明的內容對我們來說是否是一個很好的參考點？

Good question. I'll let Pranshul decide how he wants to answer that question, what we're looking for.

好問題。我會讓 Pranshul 決定他想如何回答這個問題，我們在尋找什麼。

Yeah, very good question. I think initially, we want to assess the safety and tolerability of our assets. Paul's group has spent a lot of time in -- a lot of time and thought into the design of the structure. We feel we have a strong candidate that we're bringing to clinic.

是的，非常好的問題。我認為最初，我們想要評估我們資產的安全性和耐受性。保羅的團隊花了很多時間和精力來設計結構。我們覺得我們有一個強而有力的候選者可以帶到臨床。

So the focus would be on a mesothelin-targeting agent that shows safety and tolerability. So that's the core of the Phase 1 study. We will gather data on efficacy in these tumor types, and these will be measured using RECIST criteria to measure our objective response rate. We'll be gathering other data, such as PFS data and OS data. But the fundamental of the Phase 1 study is to focus on safety and tolerability.

因此，重點將放在具有安全性和耐受性的間皮素靶向劑上。這就是第一階段研究的核心。我們將收集這些腫瘤類型的療效數據，並使用 RECIST 標準來衡量這些數據，以衡量我們的客觀緩解率。我們將收集其他數據，例如 PFS 數據和 OS 數據。但第一階段研究的基礎是關注安全性和耐受性。

All right. Thank you.

好的。謝謝。

Thank you. I'm showing no further questions in the queue at this time. I would now like to turn it back to Shrinal for closing remarks.

謝謝。目前我在隊列中沒有顯示任何其他問題。我現在想將其轉回 Shrinal 進行結束語。

Apologies. That's being handed over to Ken for closing remarks.

抱歉。內容將交給 Ken 進行閉幕致詞。

Yeah, that's great. Well, thank you very much for your time and attention today and listening to questions. And we very much look forward to reporting on progress against our milestones for the remainder of 2024. And please stay tuned, and we'll provide some updates on progress throughout the course of the year. Thank you very much.

是的，那太好了。好的，非常感謝您今天抽出寶貴的時間和注意力並聆聽問題。我們非常期待報告 2024 年剩餘時間我們里程碑的進展。請繼續關注，我們將提供全年進展的一些最新資訊。非常感謝。

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

感謝您參加今天的會議。這確實結束了該程式。您現在可以斷開連線。