Zymeworks Inc (ZYME) 2022 Q4 法說會逐字稿

Good day, ladies and gentlemen, and thank you for standing by. Welcome to the Zymeworks Fourth Quarter and Full Year 2022 Results Conference Call. At this time, all participants are in a listen-only mode. After the speakers' presentation, there will be a question-and-answer session. To ask a question during the session, you will need to press star 1 on your telephone path. At this time, I would like to turn the conference over to Mr. Jack Spinks our Investor Relations for Zymeworks. Sir, you may begin.

女士們先生們，美好的一天，感謝你們的支持。歡迎參加 Zymeworks 第四季度和 2022 年全年業績電話會議。此時，所有參與者都處於只聽模式。演講者的演講結束後，將進行問答環節。要在會議期間提問，您需要在電話路徑中按星號 1。此時，我想將會議轉交給我們 Zymeworks 投資者關係部的 Jack Spinks 先生。先生，您可以開始了。

Good afternoon, and welcome, everyone. My name is Jack Spinks, Head of Investor Relations here at Zymeworks. Today, we will discuss our fourth quarter and full year 2022 financial results as well as provide an update to our ongoing business. Before we begin, I'd like to remind you that we will be making a number of forward-looking statements during this call, including, without limitation, those forward-looking statements identified in our presentation slides and the accompanying oral commentary. Forward-looking statements are based upon 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 those risks and uncertainties, we refer you to our latest SEC filings, is found on our website and as filed with the SEC. Later in this call, Chris Astle, our Senior Vice President and Chief Financial Officer, will be discussing our financial results, including certain non-GAAP measures. A description of our GAAP measures and a reconciliation to the most directly comparable financial measures as determined in accordance with GAAP, are described in detail in our press release, which is available on our website at www.zymeworks.com under the Investor Relations tab. As a reminder, the audio and slides from this call will also be available on the Zymeworks website later today. Now I will turn the call over to Chris, our Senior Vice President and Chief Financial Officer. Chris?

下午好，歡迎大家。我叫 Jack Spinks，是 Zymeworks 的投資者關係主管。今天，我們將討論我們的第四季度和 2022 年全年財務業績，並提供我們正在進行的業務的最新情況。在我們開始之前，我想提醒您，我們將在本次電話會議期間做出一些前瞻性陳述，包括但不限於我們的演示幻燈片和隨附的口頭評論中確定的那些前瞻性陳述。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我們發展階段的公司相關的常見風險和不確定性的影響。有關這些風險和不確定性的討論，我們建議您參考我們最新的 SEC 文件，這些文件可在我們的網站上找到並提交給 SEC。在本次電話會議的後期，我們的高級副總裁兼首席財務官 Chris Astle 將討論我們的財務業績，包括某些非 GAAP 指標。我們的 GAAP 措施的描述以及與根據 GAAP 確定的最直接可比財務措施的調節在我們的新聞稿中有詳細描述，可在我們網站 www.zymeworks.com 的“投資者關係”選項卡下獲取。提醒一下，此次通話的音頻和幻燈片也將於今天晚些時候在 Zymeworks 網站上提供。現在我將把電話轉給我們的高級副總裁兼首席財務官克里斯。克里斯？

Thanks, Jack, and thank you, everyone, for joining us today for our fourth quarter and full year 2022 earnings call. As a reminder, I'd like to note that while I'll be presenting the prepared remarks today, Kenneth Galbraith, our Chair and CEO; and other members of our executive team will be available for Q&A following this portion of the call. With that, I'd like to begin today's call with an overview of our financial results, followed by a few recent developments and noteworthy updates across our business before we open the lines for Q&A. This afternoon, Zymeworks reported financial results for the fourth quarter and year ended December 31, 2022. Inox's net income for the year ended December 31, 2022, was $124.3 million or $1.90 earnings per diluted share compared to a net loss of $211.8 million for the year ended December 31, 2021. The swing from an annual net loss to net income was primarily related to revenue received from our collaboration agreement with Jazz, partially offset by increases in expenses incurred in 2022 relative to 2021. As reported, our revenue for 2022 was $412.5 million compared to $26.7 million for 2021. Revenues for both the year and most recent 3-month period ended December 31, 2022, primarily related to the $375 million in upfront payments received from Jazz as a result of the completion of the Zanidatamab licensing agreement, combined with approximately $24 million in reimbursements from Jazz for expenses incurred for Zanidatamab between October 19 and December 31, 2022. Research and development expense for the year ended December 31, 2022, was $208.6 million compared to $199.8 million for the year ended December 31, 2021. This increase of $8.8 million or 4% from the prior year related primarily to higher manufacturing and clinical trial expenses for Zanidatamab in 2022 and due to the restructuring exercise undertaken in the first quarter of 2022. These were partially offset by a decrease in expenses related to reduced preclinical Zanidatamab zovodotin-related expenses in 2022. As of October 19, 2022, Zymeworks entitled to reimbursement from Jazz for all Zanidatamab-related expenses, related to ongoing studies under the terms of the collaboration agreement finalized in Q4 2022.

謝謝杰克，也謝謝大家今天加入我們的第四季度和 2022 年全年財報電話會議。提醒一下，我想指出，雖然我今天將發表準備好的講話，但我們的主席兼首席執行官肯尼斯·加爾布雷思 (Kenneth Galbraith)；在電話的這一部分之後，我們執行團隊的其他成員將可以進行問答。有了這個，我想開始今天的電話會議，概述我們的財務業績，然後是我們業務的一些最近的發展和值得注意的更新，然後我們開放問答線。今天下午，Zymeworks 報告了截至 2022 年 12 月 31 日的第四季度和年度的財務業績。Inox 截至 2022 年 12 月 31 日止年度的淨收入為 1.243 億美元或每股攤薄收益 1.90 美元，而淨虧損為 2.118 億美元截至 2021 年 12 月 31 日的年度。從年度淨虧損到淨收入的波動主要與我們從與 Jazz 的合作協議中獲得的收入有關，部分被 2022 年相對於 2021 年發生的費用增加所抵消。據報導，我們 2022 年的收入為 4.125 億美元，而 2021 年為 2670 萬美元。截至 2022 年 12 月 31 日的年度和最近 3 個月期間的收入，主要與完成 Zanidatamab 許可後從 Jazz 收到的 3.75 億美元預付款有關協議，加上 Jazz 在 2022 年 10 月 19 日至 12 月 31 日期間為 Zanidatamab 產生的費用的約 2400 萬美元報銷。截至 2022 年 12 月 31 日止年度的研發費用為 2.086 億美元，而截至 12 月止年度為 1.998 億美元2021 年 3 月 31 日。這比上一年增加了 880 萬美元或 4%，這主要與 2022 年 Zanidatamab 的製造和臨床試驗費用增加以及 2022 年第一季度進行的重組活動有關。這些被減少部分抵消在與減少 2022 年 Zanidatamab zovodotin 臨床前相關費用相關的費用方面。截至 2022 年 10 月 19 日， Zymeworks 有權從 Jazz 報銷所有 Zanidatamab 相關費用，這些費用與根據 2022 年第四季度敲定的合作協議條款進行的正在進行的研究有關。

General and administrative expense for the year ended December 31, 2022, was $73.4 million compared to $42.6 million for the year ended December 31, 2021. This year-over-year increase of $30.8 million or 72% was driven primarily by severance and other expenses related to our reduction in force and R&D reprioritization program that occurred in early 2022 and an increase in consulting and professional fees primarily related to the company's redomicile to become a Delaware corporation, the Jazz licensing agreement and other nonrecurring project-based expenses. During 2022, the company's workforce was reduced by more than 1/3 through the reduction in force and voluntary attrition from 450 full-time employees to less than 300 full-time employees. Our cash resources consisting of cash, cash equivalents and short-term investments were $492.9 million as of December 31, 2022, largely driven by the receipt of the upfront payment from Jazz totaling $375 million in the fourth quarter. Our cash resources as of December 31, 2022, did not include $24 million in reimbursements associated with Zanidatamab-related expenses from October 19 through year-end 2022. Our licensing and collaboration agreement with Jazz completed a series of financially beneficial transformation initiatives in 2022, which we believe will fund our planned operations through at least 2026 and potentially beyond. We completed an equity offering in January 2022 comprised of a combination of common shares and prefunded warrants for gross proceeds of $115 million, which included the [exertise] in full of the underwriter's option to purchase additional shares. As of March 3, 2023, we had approximately 65.25 million shares of common stock and prefunded warrants outstanding and shares issuable pursuant to our Canadian exchangeable shares. We did not issue any shares of common stock under our ATM facility, either during 2022 or as of March 7, 2023, for the current year. In January of this year, we also issued financial guidance related to our net operating cash burn for 2023. Given the significant change in our overall net cash burn, we expect to experience this year due in large part to the reimbursement of Zanidatamab related expenses under our collaboration agreement with Jazz. We continue to expect our net operating cash balance for 2023 to be between $90 million and $120 million, including planned capital expenditures of $15 million. This cash burn guidance as well as our cash runway guidance includes forecasted expenses that are primarily related to our early R&D programs as well as incremental expenses to support our planned Phase II clinical development programs as Zanidatamab Zovodotin. For additional details on our quarterly results and for a description of our non-GAAP financial measures and a reconciliation of GAAP to non-GAAP measures, I encourage you to review our earnings release and other SEC filings as available on our website at www.zymeworks.com.

截至 2022 年 12 月 31 日止年度的一般和行政費用為 7340 萬美元，而截至 2021 年 12 月 31 日止年度為 4260 萬美元。同比增長 3080 萬美元或 72%，主要是由遣散費和其他費用推動的與我們在 2022 年初發生的裁員和研發重新排序計劃有關，以及諮詢和專業費用的增加主要與公司遷居成為特拉華州公司、Jazz 許可協議和其他基於項目的非經常性費用有關。 2022 年期間，通過裁員和自願離職，公司員工人數減少了 1/3 以上，從 450 名全職員工減少到不到 300 名全職員工。截至 2022 年 12 月 31 日，我們的現金資源（包括現金、現金等價物和短期投資）為 4.929 億美元，這主要是由於第四季度從 Jazz 收到總額為 3.75 億美元的預付款。截至 2022 年 12 月 31 日，我們的現金資源不包括從 10 月 19 日到 2022 年年底與 Zanidatamab 相關費用相關的 2400 萬美元報銷。我們與 Jazz 的許可和合作協議在 2022 年完成了一系列具有財務效益的轉型計劃，我們相信這將至少在 2026 年甚至更長時間內為我們的計劃運營提供資金。我們於 2022 年 1 月完成了一次股權發行，其中包括普通股和預先註資認股權證，總收益為 1.15 億美元，其中包括 [行使] 承銷商購買額外股份的全部選擇權。截至 2023 年 3 月 3 日，我們擁有約 6525 萬股普通股和已發行的預注資認股權證以及根據我們的加拿大可交換股票可發行的股票。在 2022 年期間或截至 2023 年 3 月 7 日，我們沒有在我們的 ATM 設施下發行任何普通股。今年 1 月，我們還發布了與 2023 年淨運營現金消耗相關的財務指導。鑑於我們整體淨現金消耗的重大變化，我們預計今年將經歷很大一部分原因是 Zanidatamab 相關費用的報銷我們與 Jazz 的合作協議。我們繼續預計 2023 年的淨運營現金餘額將在 9000 萬美元至 1.2 億美元之間，其中包括 1500 萬美元的計劃資本支出。該現金消耗指南以及我們的現金跑道指南包括主要與我們的早期研發計劃相關的預測費用以及支持我們計劃的 II 期臨床開發計劃的增量費用，如 Zanidatamab Zovodotin。有關我們季度業績的更多詳細信息以及我們的非 GAAP 財務措施的描述以及 GAAP 與非 GAAP 措施的調節，我鼓勵您查看我們的收益發布和其他 SEC 文件，這些文件可在我們的網站 www.zymeworks 上找到.com。

Now I'd like to spend a few minutes talking about our early R&D portfolio, followed by a brief discussion on Zanidatamab Zovodotin and Zanidatamab, our most advanced clinical product candidate. We reprioritized our R&D strategy early in 2022 and had an exciting and productive year with substantial progress on executing this new R&D strategy. To quickly recap, we recruited Dr. Paul Moore as our new Chief Scientific Officer in June of last year and hosted an early research and development day in October, where we previewed preclinical product candidates emerging from both our antibody drug conjugate and multi-specific platform technologies designed to overcome limitations of existing therapies. At that same event, we disclosed our 2 lead candidates for INDs by 2024, ZW171 and ZW191, both of which are on track to be submitted next year. Additionally, we set an ambitious target of progressing 5 novel and differentiated preclinical product candidates, including ZW171 and ZW191 into clinical studies by 2027. We believe that our pursuit of this goal, along with our scientific vision and path forward in the ADC and multispecific antibody space will help generate a diverse and valuable oncology product portfolio of wholly owned product candidates. In addition to developing our own internal oncology pipeline, we anticipate additional preclinical product candidates derived from our ADC and multispecific technologies to progress with resources available from potential partners and collaborators. We are continuing to evaluate opportunities to form additional collaborations and partnerships around both our publicly disclosed and confidential preclinical product candidates. This partnership strategy is important as it can help us to accelerate development and advance potential opportunities without the use of Zymeworks' shareholder capital to complement our wholly owned product pipeline. We hope to announce the completion of additional collaborations and partnerships before the end of this year for multiple preclinical product candidates. In helping further this objective, we are excited to announce the acceptance for publication of 11 abstracts at the American Association for Cancer Research, or AACR, to be presented in mid-April in Orlando, Florida. These abstracts will be made publicly available by AACR on March 14. At AACR, we will be able to share with you additional progress and preclinical data on the announced preclinical product candidates that we spoke to at our early R&D day last year as well as continued progress on our technology platforms for generating additional ADC and multispecific antibody therapeutic candidates to add to our preclinical product pipeline beyond 2024.

現在我想花幾分鐘談談我們的早期研發組合，然後簡要討論我們最先進的臨床候選產品 Zanidatamab Zovodotin 和 Zanidatamab。我們在 2022 年初重新確定了研發戰略的優先順序，並在執行這一新研發戰略方面取得了實質性進展，度過了激動人心且富有成效的一年。快速回顧一下，我們在去年 6 月聘請了 Paul Moore 博士作為我們的新首席科學官，並在 10 月舉辦了早期研發日，在那裡我們預覽了來自我們的抗體藥物偶聯物和多特異性平台的臨床前候選產品旨在克服現有療法局限性的技術。在同一次活動中，我們披露了到 2024 年 IND 的 2 個主要候選藥物 ZW171 和 ZW191，它們都有望在明年提交。此外，我們設定了一個雄心勃勃的目標，即到 2027 年將包括 ZW171 和 ZW191 在內的 5 種新穎和差異化的臨床前候選產品推進臨床研究。我們相信，我們對這一目標的追求，以及我們在 ADC 和多特異性抗體方面的科學願景和前進道路space 將有助於產生多樣化且有價值的腫瘤學產品組合，包括全資候選產品。除了開發我們自己的內部腫瘤管線外，我們預計來自我們的 ADC 和多特異性技術的更多臨床前候選產品將與潛在合作夥伴和合作者提供的資源一起取得進展。我們將繼續評估機會，圍繞我們公開披露和保密的臨床前候選產品形成更多的合作和夥伴關係。這種夥伴關係戰略很重要，因為它可以幫助我們在不使用 Zymeworks 的股東資本來補充我們全資擁有的產品線的情況下加快發展和推進潛在機會。我們希望在今年年底前宣布完成多個臨床前候選產品的額外合作和夥伴關係。為了幫助進一步實現這一目標，我們很高興地宣布美國癌症研究協會 (AACR) 接受發表 11 篇摘要，這些摘要將於 4 月中旬在佛羅里達州奧蘭多舉行。這些摘要將於 3 月 14 日由 AACR 公開。在 AACR 上，我們將能夠與您分享我們在去年早期研發日以及繼續在我們的技術平台上取得進展，以產生更多的 ADC 和多特異性抗體治療候選藥物，以增加我們 2024 年以後的臨床前產品線。

Subsequent to these presentations in Orlando, we will also plan to host our conference call to discuss the results and strategic impact these new data will have on our path forward. In addition to our in-house development efforts, we continue to have multiple active licensing agreements with key pharmaceutical and biotechnology partners. This portfolio of legacy platform partnerships, which consist of partnerships where we are required to expand little, if any, capital to advance the programs represent a significant source of past and potential future non-dilutive funding. To date, we have received approximately $180 million in upfront and milestone payments, not including any amounts received for Zanidatamab or Zanidatamab Zovodotin. Further, throughout 2023 and 2024, we expect to earn additional milestone payments under existing agreements as product candidates continue to be advanced through development stages by our partners. We also retain the ability to monetize all or a portion of the future cash flows from these agreements, pulling forward the value of future cash payments to provide an additional source of non-dilutive capital should it be needed. Here on Slide 6, we can take a moment to touch on Zanidatamab Zovodotin or [ZaniZov] for short. As you likely noticed from our earnings release issued earlier this afternoon, we are planning to continue with a data-driven development program for ZaniZov and advance into selected patient cohorts in Phase II clinical studies. This will appropriately move this product candidate forward by studying ZaniZov combination with other approved agents, especially checkpoint inhibitors with incremental clinical investment and predetermined benchmarks. Previously, we had anticipated a protocol expansion of our ongoing Phase I clinical study. However, after careful evaluation and a better understanding of both time lines and what we believe will be the most valuable to any potential future partner, thus building potentially meaningful value to our shareholders, we have chosen to proceed with separate Phase II studies to be conducted. One evaluating ZaniZov in combination with PD-1 inhibitors in non-small cell lung cancer and another in patients with breast cancer after progression on TDXD and HER2 low patients in combination with PD-1 inhibitors. With this design, we believe we can obtain the clinical data necessary to both enter into a registrational path for ZaniZov before the end of 2025 and attract an appropriate partner to assist with ex U.S. development and commercialization, which is something we currently expect would be required before moving forward into a registration pathway. We continue to consider other areas of interest for clinical development in evaluating ZaniZov with the current standard of care in HER2 amplified colorectal cancer patients, HER2 expressing gynecological cancer patients and HER2-positive gastrosophageal, adenocarcinoma or GEA.

在奧蘭多進行這些演示之後，我們還將計劃召開電話會議，討論這些新數據將對我們的前進道路產生的結果和戰略影響。除了我們的內部開發工作外，我們還繼續與主要製藥和生物技術合作夥伴簽訂多項有效許可協議。這種傳統平台合作夥伴關係的組合，包括我們需要擴展很少（如果有的話）資本來推進項目的合作夥伴關係，代表了過去和未來潛在的非稀釋性資金的重要來源。迄今為止，我們已收到約 1.8 億美元的預付款和里程碑付款，不包括為 Zanidatamab 或 Zanidatamab Zovodotin 收到的任何款項。此外，在整個 2023 年和 2024 年，隨著我們的合作夥伴繼續推進候選產品的開發階段，我們預計將根據現有協議獲得額外的里程碑付款。我們還保留了將這些協議的全部或部分未來現金流貨幣化的能力，在需要時拉動未來現金支付的價值，以提供額外的非稀釋性資本來源。在幻燈片 6 上，我們可以花點時間談談 Zanidatamab Zovodotin 或簡稱 [ZaniZov]。正如您可能從我們今天下午早些時候發布的收益報告中註意到的那樣，我們計劃繼續為 ZaniZov 實施數據驅動的開發計劃，並在 II 期臨床研究中推進選定的患者隊列。這將通過研究 ZaniZov 與其他已批准藥物的組合，特別是具有增量臨床投資和預定基準的檢查點抑製劑，適當地推動該候選產品向前發展。此前，我們曾預計我們正在進行的 I 期臨床研究的協議擴展。然而，在仔細評估和更好地理解這兩個時間線以及我們認為對任何潛在未來合作夥伴最有價值的東西，從而為我們的股東創造潛在有意義的價值之後，我們選擇繼續進行單獨的第二階段研究.一項評估 ZaniZov 聯合 PD-1 抑製劑治療非小細胞肺癌，另一項評估 TDXD 和 HER2 低患者聯合 PD-1 抑製劑治療進展後的乳腺癌患者。通過這種設計，我們相信我們可以獲得必要的臨床數據，以便在 2025 年底之前進入 ZaniZov 的註冊路徑，並吸引合適的合作夥伴來協助前美國的開發和商業化，這是我們目前預計需要的在進入註冊途徑之前。我們繼續考慮其他感興趣的臨床開發領域，以評估 ZaniZov 在 HER2擴增的結直腸癌患者、HER2表達的婦科癌症患者和 HER2陽性胃食管癌、腺癌或 GEA 中的當前護理標準。

We anticipate that our Phase II studies for ZaniZov will be implemented using a Simon's 2-stage study design. This allows us to clearly designate and define hurdle rates and stage our investment in ZaniZov going forward. We expect that the conduct of these Phase II studies will be expanded geographically to additional clinical sites in Asia and Europe to both improve the speed of patient recruitment and lower the overall clinical development cost of patient recruitment. Our newly formed regional hubs will help us provide the appropriate support for this geographic expansion of our clinical development program for ZaniZov . We continue to believe that the Phase I clinical data presented last year at ESMO at 2.5 milligrams per kilogram dosed every 3 weeks shows that ZaniZov has a differentiated tolerability profile relative to other HER2 ADCs and acceptable single-agent activity in a range of HER2-expressing tumors. The keratitis seen in our Phase I study is well characterized and primarily low grade being grade 1 or 2, which is both manageable and reversible. An appropriate dose reduction management strategy was effective in managing any patients effective with keratitis in our Phase I study without any significant discontinuation from the clinical study. Importantly, we did not see other tolerability signals of concern, common to other HER2 ADC products and consequently, an attractive part of what we believe ZaniZov can offer is the potential ability to combine with other agents currently used as standard of care in areas where we see the patient need and where we may be able to improve upon current efficacy seen with existing standards of care. Incremental investment in these Phase II studies, which are planned to begin enrolling patients in 2023 is warranted based on the clinical data generated to date and our recent interactions with KOLs and potential partners. While this [plan] represents a small component of our anticipated net cash operating burn guidance of $90 million to $120 million for 2023. We think that ZaniZov represents an important and investable opportunity worth pursuing as a differentiated HER2 ADC in post-TDXD patient population and could provide the company with the ability to retain development and commercial rights in the U.S. while working with a partner in ex U.S. markets. Finally, on ZaniZov , while we have continued to enroll and follow patients on our Phase I study treated at the recommended Phase II dose of 2.5 milligrams per kilogram every 3 weeks of monotherapy. We will be closing the weekly cohort in order to eliminate any future additional costs associated with keeping this portion of the study open. We expect to be able to present further data before the end of this year on that weekly data as well as additional monotherapy data generated since the data cut off for the 2022 ESMO presentation. However, going forward, we will be focused on opening the initial 2 Phase II studies and generating combination data as quickly as practicable. Finally, before we open things up for Q&A, I will briefly touch on Zanidatamab as we still have an exciting year ahead of us and recently presented important data at ASCO GI this January. At ASCO GI, we presented updated data from our Phase II trial evaluating Zanidatamab in frontline HER2-positive metastatic GEA. These data included a first look at Zanidatamab's overall survival data, which showed an impressive 84% overall survival at 18 months, with the median overall survival having not been reached. Further, the data included an overall confirmed objective response rate of 79%, including 3 complete responses and median progression-free survival of 12.5 months and a median duration of response of 20.4 months after 26.5 months of patient follow-up.

我們預計我們對 ZaniZov 的 II 期研究將使用 Simon 的兩階段研究設計來實施。這使我們能夠明確指定和定義門檻率，並安排我們對 ZaniZov 的投資向前發展。我們預計，這些 II 期研究的開展將在地理上擴展到亞洲和歐洲的其他臨床地點，以提高患者招募的速度並降低患者招募的總體臨床開發成本。我們新成立的區域中心將幫助我們為 ZaniZov 臨床開發計劃的地理擴張提供適當的支持。我們仍然相信，去年在 ESMO 上公佈的每 3 週給藥一次 2.5 毫克/千克的 I 期臨床數據表明，ZaniZov 相對於其他 HER2 ADC 具有差異化的耐受性特徵，並且在一系列 HER2 表達藥物中具有可接受的單藥活性腫瘤。在我們的 I 期研究中看到的角膜炎具有很好的特徵，主要是低級別的 1 級或 2 級，這是可控和可逆的。在我們的 I 期研究中，適當的劑量減少管理策略可有效管理任何有效的角膜炎患者，而不會顯著中止臨床研究。重要的是，我們沒有看到其他 HER2 ADC 產品常見的其他令人擔憂的耐受性信號，因此，我們認為 ZaniZov 可以提供的一個有吸引力的部分是潛在的能力，可以與目前在我們所在地區用作護理標準的其他藥物相結合了解患者的需求，以及我們可以在哪些方面改進現有護理標準所見的當前療效。根據迄今為止生成的臨床數據以及我們最近與 KOL 和潛在合作夥伴的互動，有必要對這些計劃於 2023 年開始招募患者的 II 期研究進行增量投資。雖然這個[計劃]代表了我們預期的 2023 年 9000 萬至 1.2 億美元的淨現金運營消耗指導的一小部分。我們認為 ZaniZov 代表了一個重要且可投資的機會，作為 TDXD 後患者群體中的差異化 HER2 ADC 值得追求，並且可以為公司提供在美國保留開發和商業權利的能力，同時與美國以外市場的合作夥伴合作。最後，在 ZaniZov 方面，我們繼續招募和跟踪 I 期研究的患者，這些患者接受的 II 期推薦劑量為每 3 週單藥治療 2.5 毫克/千克。我們將關閉每週隊列，以消除與保持這部分研究開放相關的任何未來額外費用。我們希望能夠在今年年底之前提供有關該每週數據的更多數據，以及自 2022 年 ESMO 演示數據中斷以來生成的其他單藥治療數據。然而，展望未來，我們將專注於開展最初的 2 期 II 期研究並儘快生成組合數據。最後，在我們開始問答之前，我將簡要介紹一下 Zanidatamab，因為我們還有激動人心的一年，並且最近在今年 1 月的 ASCO GI 上展示了重要數據。在 ASCO GI 上，我們展示了在 HER2 陽性轉移性 GEA 一線評估 Zanidatamab 的 II 期試驗的更新數據。這些數據包括對 Zanidatamab 總生存期數據的初步了解，該數據顯示 18 個月時的總生存率為 84%，令人印象深刻，而中位總生存期尚未達到。此外，數據包括 79% 的總體確認客觀緩解率，包括 3 例完全緩解和 12.5 個月的中位無進展生存期以及 26.5 個月的患者隨訪後的中位緩解持續時間 20.4 個月。

The regimen was manageable, tolerable and consistent with the observed safety profiles reported for other standard regimens for patients with HER2-positive GEA. We are working closely with Jazz and BeiGene to continue enrollment of patients in the Phase III randomized clinical trial, Horizon GEA01, evaluating Zanidatamab in combination with chemotherapy, plus or minus atezolizumab as a first-line treatment for HER2-expressing metastatic or advanced GEA. We continue to expect top line results from this pivotal study to be available in 2024. Additionally, last quarter, Zymeworks reported positive top line data from our Phase IIb open-label, single-arm clinical trial, Horizon-BTC-01, studying Zanidatamab as a monotherapy in patients with previously treated HER2 amplified and expressing [biliary] tract cancers. With a confirmed objective response rate of 41.3% and a median duration of response of 12.9 months in patients with HER2 amplified and expressing or IHC 2+ and 3+ disease. These data represent a potentially important step for HER2 amplify patients with BTC because Zanidatamab has the potential to be the first HER2-targeted therapy in this indication. It represents a chemotherapy-free treatment option for patients who would otherwise receive standard of care chemotherapy in second line, which typically elicits overall response rates of between 5% and 15%. Further, we expect the full results from these data to be presented at a major medical meeting in the first half of this year and look forward to confirming that presentation as soon as practicable. We remain very encouraged by these positive top line results for Zanidatamab as well as the recently presented results at ASCO GI, including the first look at overall survival data for Zanidatamab in our Phase II. With our partners, Jazz and BeiGene, we continue to work towards the potential regulatory path forward with the relevant regulatory bodies in various countries where the BTC data may support an accelerated or full approval. We will continue to work with our partners who will provide guidance at the appropriate time for any regulatory filings. While the initial development path and global regulatory interactions will be focused in BTC and GEA, the 2 most advanced indications with ongoing pivotal trials. We and our partners continue to evaluate the development path in other indications beyond BTC and GEA. We have ongoing clinical development in additional indications and remain excited about the broad potential of Zanidatamab in indications outside GI cancers. To this point, Zanidatamab is currently being used in the I-SPY platform trial for patients with HER2-expressing tumors in the neoadjuvant treatment of locally advanced breast cancer. This and other ongoing development efforts for Zanidatamab will help determine the path forward in these indications.

該方案是可控的、可耐受的，並且與針對 HER2 陽性 GEA 患者的其他標準方案報告的觀察到的安全性概況一致。我們正在與 Jazz 和 BeiGene 密切合作，繼續在 III 期隨機臨床試驗 Horizon GEA01 中招募患者，評估 Zanidatamab 聯合化療，加或減 atezolizumab 作為 HER2 表達轉移性或晚期 GEA 的一線治療。我們繼續預計這項關鍵研究的頂線結果將於 2024 年公佈。此外，上個季度，Zymeworks 報告了我們的 IIb 期開放標籤單臂臨床試驗 Horizon-BTC-01 的正面頂線數據，研究 Zanidatamab作為先前治療過的 HER2 擴增和表達[膽道] 癌患者的單一療法。在 HER2 擴增和表達或 IHC 2+ 和 3+ 疾病患者中，經證實的客觀緩解率為 41.3%，中位緩解持續時間為 12.9 個月。這些數據代表了 HER2 擴增 BTC 患者的潛在重要步驟，因為 Zanidatamab 有可能成為該適應症的第一個 HER2 靶向治療。對於原本會在二線接受標準化療的患者，它代表了一種無化療的治療選擇，通常會產生 5% 至 15% 的總體反應率。此外，我們預計這些數據的全部結果將在今年上半年的一次重要醫學會議上公佈，並期待在切實可行的情況下盡快確認該報告。我們對 Zanidatamab 的這些積極的頂線結果以及最近在 ASCO GI 上公佈的結果感到非常鼓舞，包括在我們的 II 期中首次查看 Zanidatamab 的總體生存數據。我們與我們的合作夥伴 Jazz 和 BeiGene 一起，繼續與 BTC 數據可能支持加速或完全批准的各個國家的相關監管機構一起朝著潛在的監管路徑前進。我們將繼續與我們的合作夥伴合作，他們將在適當的時候為任何監管備案提供指導。雖然最初的開發路徑和全球監管互動將集中在 BTC 和 GEA，這兩個最先進的適應症正在進行關鍵試驗。我們和我們的合作夥伴繼續評估 BTC 和 GEA 以外的其他適應症的發展路徑。我們正在進行其他適應症的臨床開發，並對 Zanidatamab 在胃腸道癌症以外的適應症中的廣泛潛力感到興奮。至此，Zanidatamab 目前正在 I-SPY 平台試驗中用於 HER2 表達腫瘤患者的局部晚期乳腺癌新輔助治療。 Zanidatamab 的這項和其他正在進行的開發工作將有助於確定這些適應症的前進道路。

Last year was an important year for the company with numerous ambitious goals that were set in January of 2022 to reset the company's strategy. As we reflect on the past year, we were able to make significant progress across multiple aspects of our business, including on the nonscientific front, where we successfully completed a redomicile to Delaware, resulting in positive inflows due to index inclusion in U.S.-based indices as well as a stock exchange listing change from the New York Stock Exchange to the NASDAQ stock market, where we better align with peers in the biotechnology sector. As we look towards 2023, we have identified 5 important pillars of value, our enterprise value framework, that we will look to advance in order to continue generating value. These 5 pillars are 2 Zanidatamab collaborations with BeiGene and Jazz, our early research and development programs, Zanidatamab Zovodotin and our legacy platform licensing portfolio. From a business and financial standpoint, we believe we are well positioned for success with our new strategy. We have sufficient cash to pursue our planned development activities with a significantly reduced net cash burn, a focused clinical program with planned Phase II studies for Zanidatamab Zovodotin and a number of exciting preclinical product candidates that we are working to progress to clinical studies with a specific focus on development of a mix of antibody-drug conjugates and multispecific antibodies. We believe this focused investment and moderated future spending when combined with the scientific expertise and people working hard behind the scenes makes for a very compelling opportunity going forward. As we remain focused on our operational goals, we will also stay true to our vision to discover, develop and commercialize novel medicines that can make a meaningful difference in the lives of patients around the world impacted by difficult-to-treat cancers and other serious diseases. To all of those who have been with us through what was a challenging 2022 for everyone investing and working in biotech. Zymeworks now looks forward to the future from a strong financial and scientific footing, and we expect to continue delivering upon these results, generating long-term value for our shareholders and ultimately improving the lives of patients by generating antibody-based therapeutics with the potential to dramatically improve on current standards of care in difficult-to-treat cancers. With that, I'd like to thank everyone for listening to our prepared remarks. And I'll turn the call over to the operator to begin the question-and-answer session. Operator?

去年對公司來說是重要的一年，公司在 2022 年 1 月制定了許多雄心勃勃的目標，以重新設定公司的戰略。回顧過去的一年，我們在業務的多個方面都取得了重大進展，包括在非科學方面，我們成功地完成了特拉華州的遷冊，由於指數被納入美國指數，導致資金流入為正以及從紐約證券交易所到納斯達克股票市場的證券交易所上市變更，我們可以更好地與生物技術領域的同行保持一致。展望 2023 年，我們確定了 5 個重要的價值支柱，即我們的企業價值框架，我們希望推進這些支柱以繼續創造價值。這 5 個支柱是 2 個 Zanidatamab 與 BeiGene 和 Jazz 的合作、我們的早期研發項目、Zanidatamab Zovodotin 和我們的傳統平台許可組合。從業務和財務的角度來看，我們相信我們已經做好準備，可以通過我們的新戰略取得成功。我們有足夠的現金來進行我們計劃的開發活動，顯著減少淨現金消耗，一個重點臨床項目，計劃對 Zanidatamab Zovodotin 進行 II 期研究，以及一些令人興奮的臨床前候選產品，我們正在努力推進臨床研究專注於抗體藥物偶聯物和多特異性抗體的開發。我們相信，這種有針對性的投資和適度的未來支出，再加上科學專業知識和幕後辛勤工作的人們，將為未來帶來非常誘人的機會。在我們繼續專注於我們的運營目標的同時，我們也將堅持我們的願景，即發現、開發和商業化新藥，這些新藥可以為世界各地受難治性癌症和其他嚴重疾病影響的患者的生活帶來有意義的改變疾病。對於所有在生物技術領域投資和工作的人來說，2022 年充滿挑戰。 Zymeworks 現在以強大的財務和科學基礎展望未來，我們希望繼續取得這些成果，為我們的股東創造長期價值，並通過產生具有潛力的基於抗體的療法最終改善患者的生活顯著提高目前治療難治性癌症的標準。至此，我要感謝大家聆聽我們準備好的發言。我會把電話轉給接線員，開始問答環節。操作員？

(Operator Instructions) Our first question or comment comes from the line of Yigal Nochomovitz from Citi.

（操作員說明）我們的第一個問題或評論來自花旗的 Yigal Nochomovitz。

So on the ZW49 now called [ZanZov], you mentioned that you're going to stop the Phase I, I believe, except for one of the cohorts. So can you just go into a little bit more detail as to the thinking behind that to why you're moving into those 2 Phase IIs, one in the non-small cell, one in the metastatic breast cancer, to get a better understanding of the shift in strategy there.

因此，在現在稱為 [ZanZov] 的 ZW49 上，你提到你將停止第一階段，我相信，除了其中一個隊列。那麼，你能否更詳細地談談這背後的想法，以及為什麼你要進入這兩個 II 期，一個在非小細胞中，一個在轉移性乳腺癌中，以便更好地了解那裡的戰略轉變。

Yes, sure. And I don't think it's as much a shift in strategy as more form over substance. So I think there was a clear preference from a regulatory perspective to initiate new combination cohorts in a Phase II format. So again, with we're trying to do a few things here. One is we're trying to reduce the patient clinical development costs because our prior costs were too high. We're trying to improve the speed of patient recruitment because I think we've been too slow. I think we need to improve the access to quality patients that we can screen for these clinical studies. And there's a number of things we've been doing about that for ourselves in that position. The #1 thing is to try and expand sites globally because the Phase I were done in the U.S., Canada and Korea, but not beyond. And I think going internationally gets to some of those points I talked about. But clearly, if we're doing filings in new countries, starting fresh for the Phase II study as opposed to amending a Phase I study is preferable. I think some of this we did over the early-stage development group, which we reorganized, definitely bring down the internal costs for these clinical development costs. And the same people in that group are preparing for 171 and 191 it needs to be followed next year in clinical trials to be commenced. And also, we're reviewing the CRO, which we have for the Phase I, [decided] we want to move forward in Phase II. And I think we could definitely accomplish some of the costs as we objectives by potentially reviewing that contract deciding it. So with all that being said, I think it's a clear preference from a regulatory perspective that we do this as Phase II. It's not going to make a difference to the size of the studies or to the timing of execution. There's also some benefits of moving forward. If we're able to generate some great data in combination with ZW49 in these multiple HER2 indications that we've already identified. I mean, [inaudible] product profile. That's our value proposition. We'd improve that. We can move much more quickly forward to a registration pathway in conjunction with a partner, as we've mentioned before in exit markets by starting in Phase II now. So I think there's some forward thinking that if we are successful and being able to move to ZW49 forward after these phases forwards, then we'll be in a better position to that even more quickly. Beyond that, we're comfortable with the advisory board and other work we've done around non-small cell lung cancer to move forward. I think with the breast cancer cohorts that makes sense. Our entire product profile to show the ZWB4 in combination with standard of care, can provide some meaningful clinical benefit in several indications with a specific focus on those patients who have progressed after GST. So those cohorts and those indications [get us out]. I think we're still going to continue to collect some additional bid in Phase I in our GEA cohort monotherapy, which I think will be useful. I think in the ovarian and in [rectal] cancer indication as we mentioned before, we did mention, I think, when we talked about this last year or earlier this year, we were waiting some view on the clinical data from the [pan-tumor] 02, especially in ovarian. And we understand that the standard of care that we're looking at is going to evolve or not. And obviously, that data internet will be forthcoming, which will be great. I think in the colorectal the HER2 amplify population, that's a really interesting patient population for us with ZW49. I think right now, we're continuing to confirm the [Epi data] around the size of that patient population because the published data has a pretty wide [standard deviation]. And also I think we're trying to make sure we understand the clear combination [of the kind of care] that we would move ahead with so we could execute a clinical development plan to get some very good data. So I think we're continuing to evaluate some of those areas, but feel comfortable moving forward with a non-small cell lung cancer cohorts and the breast cancer cohorts in both the HER2 low and in the TFC progress or field population. And Phase II, I think this is a better basis to do that in the international expansion and could provide some benefits moving much more quickly later and it does impact the timing right now.

是的，當然。而且我不認為這是戰略上的轉變，更多的是形式而不是實質。因此，我認為從監管角度來看，顯然傾向於以 II 期形式啟動新的聯合隊列。因此，我們再次嘗試在這裡做一些事情。一是我們正在努力降低患者臨床開發成本，因為我們之前的成本太高了。我們正在努力提高患者招募的速度，因為我認為我們太慢了。我認為我們需要改善我們可以篩選這些臨床研究的優質患者的獲取途徑。在那個位置上，我們一直在為自己做很多事情。第一件事是嘗試在全球範圍內擴展站點，因為第一階段是在美國、加拿大和韓國完成的，但沒有超出其他國家。而且我認為走向國際可以達到我談到的一些要點。但很明顯，如果我們在新的國家/地區進行申報，則最好重新開始 II 期研究，而不是修改 I 期研究。我認為我們在重組的早期開發小組中所做的一些工作肯定會降低這些臨床開發成本的內部成本。該組中的同一個人正在準備 171 和 191，明年需要進行臨床試驗。而且，我們正在審查第一階段的 CRO，[決定] 我們希望在第二階段向前推進。而且我認為我們肯定可以通過潛在地審查決定它的合同來實現我們目標的一些成本。因此，綜上所述，我認為從監管角度來看，我們明顯傾向於將此作為第二階段進行。它不會對研究的規模或執行時間產生影響。前進也有一些好處。如果我們能夠在我們已經確定的這些多個 HER2 適應症中結合 ZW49 生成一些很好的數據。我的意思是，[聽不清] 產品簡介。這就是我們的價值主張。我們會改進它。我們可以更快地與合作夥伴一起進入註冊途徑，正如我們之前在退出市場中提到的那樣，現在從第二階段開始。所以我認為有一些前瞻性的想法，如果我們成功並且能夠在這些階段之後向前移動到 ZW49，那麼我們將更快地處於更好的位置。除此之外，我們對顧問委員會和我們為推動非小細胞肺癌所做的其他工作感到滿意。我認為對於乳腺癌隊列來說這是有道理的。我們展示 ZWB4 與護理標準相結合的整個產品概況可以在多個適應症中提供一些有意義的臨床益處，特別關注那些在 GST 後進展的患者。所以那些隊列和那些跡象[讓我們出去]。我認為我們仍將繼續在我們的 GEA 隊列單一療法的第一階段收集一些額外的投標，我認為這將是有用的。我認為在我們之前提到的卵巢癌和 [直腸] 癌適應症中，我們確實提到過，我認為，當我們去年或今年早些時候談到這個問題時，我們正在等待對 [pan-腫瘤】02，尤其是卵巢。我們知道我們正在研究的護理標準是否會發生變化。很明顯，數據互聯網即將到來，這將是非常棒的。我認為在結直腸中 HER2 擴增人群，這對我們 ZW49 來說是一個非常有趣的患者人群。我認為現在，我們正在繼續確認關於該患者人群規模的 [Epi 數據]，因為已發布的數據具有相當大的 [標準差]。而且我認為我們正在努力確保我們了解我們將繼續推進的 [那種護理] 的明確組合，以便我們可以執行臨床開發計劃以獲得一些非常好的數據。因此，我認為我們正在繼續評估其中一些領域，但在 HER2 低和 TFC 進展或現場人群中，我們對非小細胞肺癌隊列和乳腺癌隊列的進展感到很自在。而第二階段，我認為這是在國際擴張中做到這一點的更好基礎，並且可以在以後更快地提供一些好處，並且它確實影響了現在的時機。

And just on Horizon GEA01, how much have you said there in terms of the powering of the trial? And also what is the primary comparison? Is it the doublet versus [receptive] chemo or the triplet versus receptive chemo? If you could just comment there.

就 Horizon GEA01 而言，您在試驗的動力方面說了多少？什麼是主要比較？是雙藥與[接受性]化療還是三藥與接受性化療？如果您可以在那裡發表評論。

Yes. So we did publish the atypical design and other features of the study in August of last year, and that's available on our website. We'd like to take a look at this. So, we did a more secure publication, so we did put on our websites available. So there are more details which are available there. But each of the 2 arms are independently compared to [inaudible] chemo. So that's the way it works. We did describe that in the publication so I encourage you to read that. We did also disclose there that at the point where we're going to get a PFS that we'll do an [interim] [gall-estro] at the same time and then decide what to do with that data. And we still believe we're on track that the top line data for that study will be available in 2024. And the extent that we can sharpen that guidance, we'll do that in conjunction with both Jazz and BeiGene as we move forward. §And sorry, just to add that we are continuing to follow the patients in the study that BeiGene has presented some initial data on last year on the triplet. So this is the Phase II study, the patient was running. In [first-line] GA patients with Zanidatamab chemo and [Tile PD-1]. So we did have some data last year. We've obviously recruited more patients in that study and is a much more mature-- Much longer follow-up, which means the data is much more mature. So obviously, at some point, we hope we'll see an update on that data set, which will hopefully give some further guidance as to how that triplet might be useful in patient populations, but we'll await guidance from BeiGene when that data set might be available, and they're also still continuing to follow the Phase II study in first-line breast cancer with Zanidatamab and Docetaxel, which we also talked about, presented last year. And obviously, we have more patients enrolled in the longer follow-up. So we'll be looking for BeiGene to guide on when those 2 data sets might be available, but specifically the triplet in Phase II with more mature data, longer follow-up, may be better understanding or guidance of where that might be useful in this patient population. So we'll wait the guidance of BeiGene.

是的。所以我們確實在去年 8 月發布了該研究的非典型設計和其他特徵，這些可以在我們的網站上找到。我們想看看這個。所以，我們做了一個更安全的發布，所以我們確實在我們的網站上提供了。所以那裡有更多詳細信息。但是，這 2 個臂中的每一個都獨立地與 [聽不清] 化療進行了比較。這就是它的工作方式。我們確實在出版物中對此進行了描述，因此我鼓勵您閱讀該內容。我們也在那裡透露，在我們將獲得 PFS 的時候，我們將同時進行 [臨時] [gall-estro]，然後決定如何處理這些數據。而且我們仍然相信我們正在走上正軌，該研究的頂級數據將在 2024 年可用。以及我們可以加強該指導的程度，我們將在前進的過程中與 Jazz 和 BeiGene 一起做到這一點。 § 抱歉，我想補充一點，我們將繼續跟踪研究中的患者，百濟神州在去年提供了一些關於三胞胎的初步數據。所以這是 II 期研究，患者正在跑步。在使用 Zanidatamab 化療和 [Tile PD-1] 的 [一線] GA 患者中。所以去年我們確實有一些數據。顯然，我們在那項研究中招募了更多患者，而且更成熟——更長的隨訪時間，這意味著數據更成熟。所以很明顯，在某個時候，我們希望我們能看到該數據集的更新，這將有望就該三聯體如何對患者人群有用提供一些進一步的指導，但我們將等待百濟神州的指導，當這些數據出現時set 可能可用，而且他們還在繼續跟踪 Zanidatamab 和多西紫杉醇一線乳腺癌的 II 期研究，我們也談到了去年提出的。顯然，我們有更多的患者參加了更長時間的隨訪。因此，我們將尋找 BeiGene 來指導這兩個數據集何時可用，但特別是 II 期的三聯體具有更成熟的數據、更長的隨訪時間，可能會更好地理解或指導哪些地方可能有用這個患者群體。所以還是等百濟神州的指導吧。

Our next question or comment comes from the line of James Shin from Wells Fargo.

我們的下一個問題或評論來自富國銀行的 James Shin。

A quick question on the Horizon GEA study. I'm looking at a comparator KEYNOTE-811. Where they -- it looks like they really enriched for PD-L1 high and HER2 3+ patients. Can you say anything on whether Horizon GEA will have a more even mix of PD-1 and HER2-positive patients? And then I got a follow-up.

關於 Horizon GEA 研究的快速提問。我正在查看比較器 KEYNOTE-811。他們在哪裡——看起來他們真的豐富了 PD-L1 高和 HER2 3+ 患者。你能說說 Horizon GEA 是否會有更均勻的 PD-1 和 HER2 陽性患者組合嗎？然後我得到了跟進。

Yes. Well, again, for 1, we're not enriching for PD-L1 status. So it will hopefully be a more recruitment, more of a perspective of real world how these patients show up for gastric acid junction and esophageal patients that are in our study. And we'll obviously break that out as a prespecified subpopulation to understand what the impact is on patient populations on [VA] status with the PD-1 is involved. We haven't seen that as the K11 data, but eventually, we'll hopefully see that we can -- KOLs can understand the impact of that patient population. It does look like it is skewed a little bit, of a way with once that has been [IC3 +]. I'm not sure how that happened or was that will be the case when you see the full patient population versus the cohort of patients that was published to support the accelerated approval.

是的。好吧，再一次，對於 1，我們沒有豐富 PD-L1 狀態。因此，希望這將是一次更多的招募，更多的是從現實世界的角度來看這些患者如何出現在我們研究中的胃酸交界處和食管患者中。我們顯然會將其分解為預先指定的亞群，以了解涉及 PD-1 對 [VA] 狀態對患者人群的影響。我們還沒有將其視為 K11 數據，但最終，我們希望看到我們能夠——KOL 能夠理解該患者群體的影響。它看起來確實有點偏斜，有點像曾經 [IC3 +]。當你看到完整的患者群體與為支持加速批准而發布的患者隊列時，我不確定這是怎麼發生的或者會是這種情況。

And then for the ZW49's breast indications, what are the potential [cabo] partners that you would explore with ZW49 or is that still sort of under wraps?

然後對於 ZW49 的乳房適應症，您將與 ZW49 探索哪些潛在的 [cabo] 合作夥伴，或者這仍然是保密的？

Yes. It's still under wrap. I think we're -- we said probably all we can about the non-small cell lung cancer and breast cancer indications. We want to get those studies up and running and get more details up on [controls.gov] as soon as we can. I think once it's up there, then we'll be able to answer answer additional questions. We're obviously looking to use ZW49 in combinations where we can. And that will be beyond [pembro] where we can. So I think we just have to wait until [control.gov] but we think that's the value proposition now that ZW49 [BD, HER2 ADC] of choices in combination potentially after progression on TDSC in multiple indications in a meaningful way in a number of those indications. And that's what we're targeting. That's the value proposition. That's our target product profile. So we define ways to test that hypothesis. And you [inaudible] efficiently from a cost perspective we can. And if we see something that's going to be [meaningful] there then be able to partner quickly and move forward with the registration strategy for is we can.

是的。它仍在保密中。我認為我們——我們可能已經盡我們所能談論非小細胞肺癌和乳腺癌的適應症。我們希望盡快啟動和運行這些研究，並在 [controls.gov] 上獲得更多詳細信息。我想一旦它在那裡，我們就可以回答其他問題。我們顯然希望盡可能組合使用 ZW49。這將超出 [pembro] 我們力所能及的範圍。所以我認為我們只需要等到 [control.gov] 但我們認為這是價值主張，因為 ZW49 [BD，HER2 ADC] 的選擇可能在 TDSC 進展後以多種有意義的方式在多種適應症中組合那些跡象。這就是我們的目標。這就是價值主張。這是我們的目標產品概況。因此，我們定義了檢驗該假設的方法。從成本的角度來看，您 [聽不清] 效率很高，我們可以。如果我們看到一些[有意義的] 事情，那麼我們就可以快速合作並推進註冊策略。

Can I ask just one question on the ISP addition of Zanidatamab. It's a really interesting study design where treatments get added and removed based on their efficacy. So and it's in [enlargment], is this something that's being handled by Chad and partners? Or is that something that you guys were working on prior to handing the Zanidatamab?

我能問一個關於 Zanidatamab 的 ISP 添加的問題嗎？這是一個非常有趣的研究設計，其中根據療效添加和刪除治療。那麼，在 [擴大] 中，這是乍得和合作夥伴正在處理的事情嗎？或者這是你們在交付 Zanidatamab 之前正在做的事情？

This is a separate study group testing, obviously, multiple different agents. It's a really -- it's a -- we were having some discussions last year, about doing that. We obviously waited until we completed the Jazz collaboration to allow Jazz to apply on that decision. And it's the first thing they did after the collaboration, so probably tells you a little bit about maybe some interest. But I think it's a really -- I think we've always hypothesized that Zanidatamab's best application was in the earliest treatment cycle that we can find specific populations. And I think you've seen that in our data with BeiGene last year and is [Zaniprostal] for first-line breast cancer with the over 90% for more. So pretty interesting. And I think we're interesting to see what comes out of this [neoadjuvant] study. I think it's this platform that they have an is [i52] now. It was a pretty interesting way to test multiple agents in a way that I think can provide some interesting data back to a sponsor to then decide what to do with that data from a registration strategy.

這是一個單獨的研究小組測試，顯然是多種不同的代理。這真的 - 這是 - 我們去年就這樣做進行了一些討論。顯然，我們等到完成與 Jazz 的合作後才允許 Jazz 申請該決定。這是他們在合作之後做的第一件事，所以可能會告訴你一些關於他們可能感興趣的事情。但我認為這是一個真正的——我認為我們一直假設 Zanidatamab 的最佳應用是在我們可以找到特定人群的最早治療週期中。我想你已經在我們去年與 BeiGene 的數據中看到了這一點，並且是 [Zaniprostal] 用於一線乳腺癌，超過 90% 用於更多。非常有趣。我認為我們很想看看這項 [新輔助] 研究的結果。我認為他們現在擁有的平台是 [i52]。這是一種非常有趣的測試多個代理的方式，我認為可以將一些有趣的數據返回給贊助商，然後決定如何從註冊策略中處理這些數據。

Our next question or comment comes from the line of Stephen Willey from Stifel.

我們的下一個問題或評論來自 Stifel 的 Stephen Willey。

Maybe just another quick one on the projected Horizon GEA disclosure in '24. Are you still planning on completing enrollment before the end of '23? And I think in the European trial register, there is a suggestion that the primary PFS analysis is expected to occur within a month of the last patient being randomized. I guess, is that a description something that you would characterize as still being accurate?

也許只是另一個關於 24 年預計 Horizon GEA 披露的快速信息。您是否仍計劃在 23 年底之前完成註冊？我認為在歐洲試驗登記冊中，建議主要 PFS 分析預計將在最後一名患者被隨機分配後的一個月內進行。我想，您認為這種描述仍然準確嗎？

Yes. I think you've seen a change in our guidance since the Jazz Partnership, which is not unusual. And Jazz does like to guide on availability of top line data versus patient enrollment. So our guidance will be the top line data will be available in 2024. And to the extent that we can sharpen that guidance with Jazz and BeiGene, then we'll do that to be more specific than the calendar year. But that's the guidance right now. We won't give anything beyond that. I think you will see [infant] trial in European registry, a number of different other data points around PFS or completion study. And we just won't comment on that further than just sticking to the -- We're on track right now to get top line data in 2024 from that study, and that's really great, and we're working to do that as quickly as we can.

是的。我想你已經看到自爵士合作夥伴關係以來我們的指導發生了變化，這並不罕見。 Jazz 確實喜歡指導頂線數據的可用性與患者登記。因此，我們的指導將是 2024 年提供的頂級數據。如果我們可以通過 Jazz 和 BeiGene 加強該指導，那麼我們將比日曆年更具體。但這就是現在的指導。除此之外，我們不會給任何東西。我想你會在歐洲登記處看到 [嬰兒] 試驗，圍繞 PFS 或完成研究的許多不同的其他數據點。我們只是堅持——我們現在正按計劃從這項研究中獲得 2024 年的頂級數據，這真的很棒，我們正在努力盡快做到這一點盡我們所能。

And then maybe just a question for Chris with respect to just clarity on [Zane] related R&D spend in '23. I know the quarterly numbers here have been fairly lumpy. I guess, if you look at the last 3 quarters, specifically, is that lumpiness something that we should expect to continue into 2023? Or have you guys done some of the necessary manufacturing work such that, that should kind of smooth out a little bit as we get into '23 with respect to just thinking about how the R&D reimbursement flows to the top line.

然後可能只是克里斯關於 23 年 [Zane] 相關研發支出的清晰度的問題。我知道這裡的季度數字相當不穩定。我想，如果你看看過去 3 個季度，具體來說，我們應該預計這種情況會持續到 2023 年嗎？或者你們是否完成了一些必要的製造工作，以便在我們進入 23 年時考慮研發報銷如何流向頂線，這應該會稍微平滑一些。

Yes. Thanks for the question. So yes, we did have some lumpiness through 2022 as we were undertaking some of the manufacturing run. A lot of that kind of expense is behind us now. As we go into 2023, there will still be some ebbs and flows. We won't be guiding on specific numbers for each individual quarter. But it's worth noting that as we incur expenses within a quarter, the reimbursement from Jazz will actually come back in the following quarter. So there'll be a mismatch between the P&L and the cash flow from quarter-to-quarter as we advance through 2023. So there will still be some quarter-to-quarter shifting that we can anticipate as we go forward.

是的。謝謝你的問題。所以，是的，到 2022 年我們確實遇到了一些困難，因為我們正在進行一些製造活動。很多這樣的費用現在已經過去了。當我們進入 2023 年時，仍然會有一些潮起潮落。我們不會指導每個季度的具體數字。但值得注意的是，由於我們在一個季度內發生費用，Jazz 的報銷實際上會在下一個季度回來。因此，隨著我們前進到 2023 年，損益表與季度間的現金流量之間將存在不匹配。因此，隨著我們的前進，我們仍然可以預期會有一些季度間的變化。

Okay. So that Jazz reimbursement comes a quarter in arrears that?

好的。那麼說爵士隊的報銷是拖欠了一個季度嗎？

That's correct, yes.

沒錯，是的。

Okay. And then maybe just lastly, I guess, does the disclosure of HER2 [CLIMB-02] data, which is looking at Tucatinib/Kadcyla and, I guess, mostly second-line patients, but I think a lot of the KOL conversations we've had would suggest that that's maybe a regimen that gets institutionalized post in the HER2 if that data looks good. Does that data set at all kind or change your thoughts around ZW49 in breast cancer?

好的。然後也許最後，我猜，是 HER2 [CLIMB-02] 數據的披露，它正在研究 Tucatinib/Kadcyla，我想，主要是二線患者，但我認為很多 KOL 對話我們'我們曾建議，如果數據看起來不錯，這可能是一種在 HER2 中製度化的方案。該數據是否完全改變了您對 ZW49 治療乳腺癌的看法？

I'm not sure entirely it does yet. I mean we obviously look at all data and evolving data and what impact it might have on commercial opportunities or development pathways or regular pathways for the program. [inaudible] and ZW49, -- and I think you need to pay tech to that and try to react. I think from our perspective, our value proposition and our target product profile, ZW49, I don't think is any different, which is we need to show the ability to combine with better care and show meaningfully clinical meaningful benefit in more than one indication, some multiple indications, several in this case. And I think in breast cancer, we still need to see what that data looks like. We need to see how it looks like in HER2-low population, and we need to look at what it looks like specifically in the patients who progress post [TXD] and hopefully, in a quality of patient that doesn't have 11 or 12 or 13 prior therapies as we did in some of our Phase I data. So I still think it's a pretty interesting indication for us in breast cancer even with some evolving data, you have done enough advisory board work with KOLs, but we understand where the bit could be for ZW49 as agent. I think we've done enough potential partnering discussions to know what value will be paid for data generated. I think for both non-small full lung cancer and breast cancer, those are just keep core cohort of patients that we think to prove our target product profile ZW49. We have the opportunity to do that with additional indications inside the envelope of how much investment we want to make in the time frame we have to make that under, then we'll do that.

我還不確定它是否完全如此。我的意思是，我們顯然會查看所有數據和不斷變化的數據，以及它可能對商業機會或發展路徑或程序的常規路徑產生什麼影響。 [聽不清] 和 ZW49，-- 我認為你需要為此支付技術費用並嘗試做出反應。我認為從我們的角度來看，我們的價值主張和我們的目標產品概況，ZW49，我認為沒有任何不同，這是我們需要展示與更好的護理相結合的能力，並在多個適應症中展示有意義的臨床意義，一些多種適應症，在這種情況下有幾種。我認為在乳腺癌方面，我們仍然需要看看這些數據是什麼樣的。我們需要看看它在 HER2-low 人群中的樣子，我們需要看看它在 [TXD] 後進展的患者中的具體情況，希望在沒有 11 或 12 的患者中或我們在某些 I 期數據中所做的 13 種先前療法。所以我仍然認為這對我們來說是一個非常有趣的乳腺癌跡象，即使有一些不斷發展的數據，你已經與 KOL 做了足夠的顧問委員會工作，但我們知道 ZW49 作為代理人的位置。我認為我們已經進行了足夠多的潛在合作討論，以了解將為生成的數據支付多少價值。我認為對於非小細胞全肺癌和乳腺癌，這些只是我們認為可以證明我們的目標產品概況 ZW49 的核心患者群體。我們有機會做到這一點，並在我們必須在必須做出的時間框架內進行多少投資的信封內附加指示，然後我們會這樣做。

Our next question or comment comes from the line of Brian Cheng from JPMorgan.

我們的下一個問題或評論來自摩根大通的 Brian Cheng。

It seems that you have a couple of presentations coming up at AACR next month. So what should our focus be there from your presentation and your call? Maybe you can give us part of the view on just expectation, that would be great.

看來你下個月要在 AACR 上做幾個演講。那麼，從您的演講和電話會議中，我們的重點應該是什麼？或許你可以給我們一些關於公正期望的觀點，那會很棒。

I think everything... That's a positive. I think from our perspective, there's some -- I think we're trying to showcase both the next products that will come out of the clinic next year, so that's really important for us as well as continuing to show what the platform is capable of doing for products beyond that because we're going to pick our targets and our products that we're going to file in 2025 this year. So we want people to understand both the next product coming in and the pocket itself. We've got additional new data we've generated since our R&D Day presentation in October. So we'll try and highlight the new and additional data, which has been developed, which I think adds hopefully to folks understanding of what we're doing that's differentiated and why we're doing and why we think we'll be successful with the product formats and the targets that we've selected as well as the platform's ability to continue to generate these 5 new INDs in the next 5 years, including [179.9] next year, that will all be novel diversified on both sides of the [RV] portfolio, both [multi-cabine] therapeutics and ADCs as well as all the will be differentiated and meaningful assets that we can keep unencumbered and [for sale] as long as possible. So I think there will be a whole lot of things there between products and the 2 platforms that we're working right now. There's also 1 on ZW49 and there's one that's unrelated to that. And those will be as abstracts in a little over up week so I think by AACR. So we'll be able to answer more of that question as those abstracts are released. And the next week or so. And then beyond that, obviously, we'll have more sustained information available on the posters for all of those.

我認為一切......這是積極的。我認為從我們的角度來看，有一些 - 我認為我們正在嘗試展示明年將在診所推出的下一款產品，所以這對我們來說非常重要，同時繼續展示該平台的功能為超出此範圍的產品做，因為我們將選擇我們將在今年 2025 年提交的目標和產品。因此，我們希望人們了解即將推出的下一款產品和口袋本身。自 10 月份的研發日演示以來，我們已經獲得了額外的新數據。因此，我們將嘗試突出顯示已開發的新數據和其他數據，我認為這些數據有望增加人們對我們正在做的事情的差異化理解以及我們為什麼這樣做以及為什麼我們認為我們會成功我們選擇的產品形式和目標以及該平台在未來 5 年內繼續產生這 5 個新 IND 的能力，包括明年的 [179.9]，這些都將在 [ RV] 投資組合，包括 [多艙] 療法和 ADC 以及所有將是差異化和有意義的資產，我們可以盡可能長時間地保持不受約束和 [待售]。所以我認為產品和我們現在正在使用的兩個平台之間會有很多東西。 ZW49 上還有 1 個，還有一個與此無關。這些將在一周多一點後作為摘要，所以我認為是 AACR。因此，隨著這些摘要的發布，我們將能夠回答更多的問題。下週左右。然後除此之外，顯然，我們將在所有這些海報上提供更多持續信息。

And maybe just one follow-up on the [ZaniZov] side. You talked about how the importance of partnership to this program. And it seems that you are already in discussion with a couple of potential partners. When do you think that it will be a good time to bring in a partner for ZAniZov ? Is there a bar that you need to hit for the Phase II that you're doing in NSCLC and also metastatic breast that you need to hit before these partners jumping in?

也許只是 [ZaniZov] 方面的一項後續行動。您談到了夥伴關係對該計劃的重要性。您似乎已經在與幾個潛在合作夥伴進行討論。你認為什麼時候是為 ZAniZov 引進合作夥伴的好時機？在這些合作夥伴加入之前，您是否需要為您在 NSCLC 中進行的 II 期以及轉移性乳腺癌達到一個標準？

Good question. I mean, obviously, we do not have clinical data in combination with other spend of care. So that's a big part of the value proposition for ourselves and partners as we'd like to generate that data. Obviously, having early part of the discussion is great because it helps design the [inaudible] program. So we like doing that. I think our current investment thesis around 249 is it's a strategic asset, it's not core to the 5 and 5 strategy, but we think it's still be viable assets that we'd like to invest incrementally in at this Phase II clinical development stage. The goal after that is to get an ex U.S. partner to work with us. If we get clinical data, which shows that the data should go forward. We'd like the terms of that deal to be valuable enough to fund the potential for us to retain the U.S. commercial rights and develop that further to market off of the partnering deal and not off our balance sheet. So we have that data that supports a partner being able to have a transaction, which is valuable enough to be able to undertake that as well as have clinical data to business ourselves that it's a reasonable undertaking to retain the U.S. rights for further development and commercialization of standings ourselves. And so we also have to convince ourselves. There is a potential that we could do a global licensing deal with one party if that was attractive to us because again, [ZAniZOv] doesn't affect the 5 and 5 strategy we have for the non-HER2 assets that we're generating behind [Zani] and ZaniZov , so to get that, I believe we need some indication as I mentioned, that it will ZW49 can be effectively combined with better care in indications that matter and show some interesting signals of efficacy to show there's a registration pathway for that agent to be a second-line agent or via second choice HER2-ADC, behind TDSP, which is very commercially attractive, especially in non-small cell lung cancer and the breast cancer indications as well as some of the other ones that were still still evaluating. So I think some of that combination data is going to be necessary to convince a partner on the value that we'd be looking for, but also to convince ourselves, that's a worthwhile asset to retain the U.S. rights.

好問題。我的意思是，很明顯，我們沒有結合其他護理費用的臨床數據。因此，這是我們自己和合作夥伴的價值主張的重要組成部分，因為我們希望生成這些數據。顯然，儘早參與討論非常好，因為它有助於設計 [聽不清] 程序。所以我們喜歡這樣做。我認為我們目前關於 249 的投資論點是它是一種戰略資產，它不是 5 和 5 戰略的核心，但我們認為它仍然是我們希望在這個 II 期臨床開發階段逐步投資的可行資產。之後的目標是讓前美國合作夥伴與我們合作。如果我們得到臨床數據，這表明數據應該向前發展。我們希望該交易的條款具有足夠的價值，能夠為我們保留美國商業權利的潛力提供資金，並進一步發展該權利以在合作交易之外而不是在我們的資產負債表之外進行營銷。因此，我們擁有支持合作夥伴能夠進行交易的數據，這些數據非常有價值，足以讓我們能夠進行交易，並且我們自己擁有臨床數據，表明保留美國權利以進行進一步開發和商業化是一項合理的承諾我們自己的排名。所以我們也必須說服自己。如果這對我們有吸引力，我們有可能與一方達成全球許可協議，因為 [ZAniZOv] 不會影響我們對我們在背後產生的非 HER2 資產的 5 和 5 策略[Zani] 和 ZaniZov，所以要做到這一點，我相信我們需要一些指示，正如我提到的那樣，它將 ZW49 可以有效地與更重要的指示相結合，並顯示一些有趣的療效信號，以表明有一個註冊途徑該藥物是二線藥物或通過第二選擇 HER2-ADC，僅次於 TDSP，這在商業上非常有吸引力，特別是在非小細胞肺癌和乳腺癌適應症以及其他一些仍然存在的適應症中還在評估。因此，我認為其中一些組合數據對於讓合作夥伴相信我們正在尋找的價值是必要的，同時也讓我們自己相信，這是保留美國權利的有價值的資產。

Our next question comment comes from the line of Charles Yu from Guggenheim Partners.

我們的下一個問題評論來自 Guggenheim Partners 的 Charles Yu。

My first one, perhaps on Zanidatamab in front-line gastric cancer. I'm kind of wondering, given that you've had that recent [ZaniZov] chemo data earlier this year as well as what we saw from ASCO of '22 last year from Beijing. I guess with the potential update from the single one Phase II later this year, any color around like how much more confidence we could obtain around the potential additive clinical benefit of layering on a PD-1 on top of your regimen?

我的第一個，也許是關於 Zanidatamab 一線胃癌。我有點想知道，鑑於你今年早些時候已經獲得了最近的 [ZaniZov] 化療數據，以及我們去年從北京的 22 年 ASCO 中看到的數據。我猜想隨著今年晚些時候單個 II 期的潛在更新，我們可以對在您的治療方案之上疊加 PD-1 的潛在附加臨床益處獲得多少信心？

Yes. I mean, the easiest way to answer that question would be to complete the Phase III study is going on now, which is fully randomized to 1:1:1 [tetris] chemo, does any chemo doublet and the triplet including making [Tempo], so the best way for us to answer that question is to incur all the patients finished the study, redose TFS and interim OS look at the subpopulation analysis that exists in the study that's prespecified to be able to answer that question. That's what we're working towards as expeditiously as we can. Obviously, the data we put in January, it's pretty encouraging to KOLs and ourselves and Jazz and BeiGene on the doublet. Hopefully, we'll get a chance for an update on additional data from the triplet that BeiGene put out last year and get some more understanding of what that looks like. You have more -- there's going to be more patient numbers than that. It's a long-term follow-up. So it might be something more to read into that. But obviously, the reason we're doing a large multinational, randomized study is to try and provide clarity on the answer to that question that you have.

是的。我的意思是，回答這個問題最簡單的方法是完成現在正在進行的 III 期研究，該研究完全隨機分配給 1:1:1 [tetris] 化療，做任何化療二聯體和三聯體，包括製作 [Tempo] ，所以我們回答這個問題的最好方法是讓所有患者完成研究，重新服用 TFS 和臨時 OS 查看研究中存在的預先指定能夠回答該問題的亞群分析。這就是我們正在努力盡快實現的目標。顯然，我們在 1 月份提供的數據，對 KOL 和我們自己以及 Jazz 和 BeiGene 來說是非常鼓舞人心的。希望我們能有機會更新百濟神州去年發布的三聯體的額外數據，並進一步了解它是什麼樣子的。你有更多 - 患者人數會比這更多。這是一個長期的跟進。所以它可能需要更多的閱讀。但很明顯，我們進行一項大型跨國隨機研究的原因是試圖為您所提出的問題提供清晰的答案。

Got it. Great. And maybe one more question on [ZaniZov], perhaps a bit of a follow-up as to something that's already been kind of asked a bit. But during your prepared remarks, I think you had mentioned something about the predetermined benchmarks that could justify further development beyond the Phase IIs and lung as well as post-and-HER2 breast cancer. Any additional color around what those could possibly be? Or how -- what was your thinking was in generating some of those benchmarks?

知道了。偉大的。也許還有一個關於 [ZaniZov] 的問題，也許是對已經有人問過的問題的一些跟進。但在你準備好的發言中，我認為你已經提到了一些關於預定基準的事情，這些基準可以證明在 IIs 期和肺癌以及 HER2 後和 HER2 乳腺癌之後的進一步發展是合理的。那些可能是什麼的任何其他顏色？或者如何 - 您在生成其中一些基準時的想法是什麼？

We've obviously like to start with some creative termination of what does clinically meaningful data look like in combination in the indications that we're in study. So we have some data that we've predetermined that we think would be meaningful and would be encouraging to attract next to a partner and would be encouraging for us to think about retaining the U.S. rights to any to to further development with the proceeds from an ex-U.S. partnership and use that as our first commercial on-trade in the U.S. So we're pretty proven that ahead of time, which is a really good process to work through. It's obviously totality of data matters and quality of patients and quality of data matters. But those are all predetermined the same way that others will do. And I think once we generate that data will have some ideas of what we think about moving forward or which indications makes the most sense to move forward. We've done a lot of work since I got here a year ago on looking at the indication, the commercial market research, the ad boards. We just did one recently in Japan in January, which we weren't able to do earlier because of Covid. So I think we have a pretty good sense from potential partner discussions and our KOL interactions of where ZW49 would have to generate data to be a fit for moving forward past.

我們顯然希望從一些創造性的終止開始，看看臨床上有意義的數據在我們正在研究的適應症中看起來是什麼樣子。因此，我們有一些我們已經預先確定的數據，我們認為這些數據是有意義的，並且會鼓勵我們吸引下一個合作夥伴，並且會鼓勵我們考慮保留美國對任何進一步發展的權利前美國合作夥伴關係並將其用作我們在美國的第一個商業交易所以我們已經提前證明了這一點，這是一個非常好的工作過程。這顯然是數據問題和患者質量以及數據質量問題的總和。但這些都是預先確定的，就像其他人會做的一樣。而且我認為，一旦我們生成該數據，就會對我們對前進的想法或哪些跡像對前進最有意義有一些想法。自從我一年前來到這里以來，我們已經做了很多工作來研究適應症、商業市場研究和廣告牌。我們剛剛在 1 月份在日本做了一個，由於 Covid，我們無法更早地做到這一點。因此，我認為我們從潛在合作夥伴的討論和我們的 KOL 互動中非常了解 ZW49 必須在何處生成數據以適合向前推進。

Thank you. Again, ladies and gentlemen, if you have a question or comment at this time on -- our next question or comment comes from the line of Andrew Berens from SVB Leerink.

謝謝。再次，女士們，先生們，如果您此時有問題或評論 - 我們的下一個問題或評論來自 SVB Leerink 的 Andrew Berens。

A couple of questions for me on the [inaudible] combination strategy of Checkpoint. Can you share any preclinical data that you have to support combination strategy? Do you have any concerns that keratitis could be exacerbated by immunotherapy as [ocular tox], a known side effect with checkpoint inhibitors? And then what do you think the regulatory strategy will eventually be demonstrate that GW Board now will be added to the background efficacy you would see with checkpoint inhibitor load.

關於 Checkpoint 的 [聽不清] 組合策略，我有幾個問題。您能否分享任何支持聯合策略的臨床前數據？您是否擔心角膜炎會因 [眼部毒素] 等免疫療法而惡化，這是檢查點抑製劑的已知副作用？然後，您認為監管策略最終將證明 GW Board 現在將添加到您在檢查點抑製劑負載中看到的背景功效。

Yes. Good question. I think you've disclosed any of the preclinical data we would have on the combination. We don't believe there will be any , as you said, any further impact on Keratitis but it's one of the reasons you run combination studies in cohorts and [inaudible]. So we'll do that to be able to confirm that. Obviously, one of the benefits of ZW29 is a HER2 is that the tolerability issues that we have to deal with are limited to grade 1 and grade 2 keratitis, which don't cause a significant discontinuation of patients under clinical study and don't provide a substantial amount of dose reduction. Beyond that, we don't have [upreneuropathy, droneumonitis] or we haven't seen any signals of that. So obviously, we think the tolerability profile means that you can provide an effective combination without overlapping toxicities. And we think there may be some synergies between P1 and ZW49 with the [Oristano] payload and that might be from a mechanism standpoint. We will have one abstract at AACR around some initial thoughts around the mechanism of ZW49 that might provide some additional information to that. Obviously, moving forward in non-small cell lung cancer, I think you wanted to use there in a variety of different indications, including with the known alpha mutations. So there's some good data already on existing around the use of those agents that indication. We obviously have to show that adding ZW49 to that if we want specifically [inaiduble] the population provides a benefit for partners. So that's a part of what we're doing in the design of the cohort that we have in both the HER2 expressing amplifier 2 mutant population in non-small cell lung cancer. In addition, on the breast cancer side, P1 not been very effective in indices indication study in breast cancer, but down to see if there is a [benefit to e9PD-1]. And if you want to be more useful and education because of this critic effect that might occur with the rates and PD-1. We'd like to explore that well for that clinically and look at that data to see if that's accurate or not.

是的。好問題。我認為您已經披露了我們可能擁有的關於該組合的任何臨床前數據。正如您所說，我們不相信會對角膜炎產生任何進一步的影響，但這是您在隊列中進行聯合研究和 [聽不清] 的原因之一。所以我們將這樣做以確認這一點。顯然，ZW29 的一個好處是 HER2 是我們必須處理的耐受性問題僅限於 1 級和 2 級角膜炎，這不會導致臨床研究中的患者顯著停藥並且不提供大量減少劑量。除此之外，我們沒有 [upreneuropathy, droneneumonitis] 或者我們沒有看到任何跡象。很明顯，我們認為耐受性特徵意味著您可以提供有效的組合而不會出現重疊毒性。我們認為 P1 和 ZW49 與 [Oristano] 有效載荷之間可能存在一些協同作用，這可能是從機制的角度來看的。我們將在 AACR 上圍繞 ZW49 機制的一些初步想法進行摘要，這可能會為此提供一些額外的信息。顯然，在非小細胞肺癌方面取得進展，我認為您想將其用於各種不同的適應症，包括已知的 alpha 突變。因此，已經有一些關於使用這些指示劑的良好數據。我們顯然必須證明，如果我們特別想要[無法解釋]人口，那麼將 ZW49 添加到其中可以為合作夥伴帶來好處。因此，這是我們在非小細胞肺癌中表達 HER2 放大器 2 突變體群體的隊列設計中所做工作的一部分。另外，在乳腺癌方面，P1在乳腺癌的指標適應症研究中不是很有效，但要往下看是否有[benefit to e9PD-1]。如果你想變得更有用和受教育，因為這種批評效應可能會隨著利率和 PD-1 發生。我們想在臨床上探索那個井，並查看該數據以確定它是否準確。

Our next question or comment comes from the line of David Martin from Bloom Burton.

我們的下一個問題或評論來自 Bloom Burton 的 David Martin。

First question, regarding the Phase II indications for ZW49, when you presented Phase I data at ESMO last year, I think there was one lung cancer patient there were relatively few in HER2 failures and a few HER2 low patients. Post that presentation, did you then kind of focus your recruitment on patients that the Phase II characteristics? And will we see larger cohort or larger groups of those patients in the updated data later this year?

第一個問題，關於 ZW49 的 II 期適應症，當你去年在 ESMO 上展示 I 期數據時，我認為有一名肺癌患者 HER2 失敗相對較少，還有一些 HER2 低患者。發布該演示文稿後，您是否將招募重點放在具有 II 期特徵的患者身上？我們會在今年晚些時候的更新數據中看到更大的隊列或更大的患者群體嗎？

Yes, Steve. That's accurate. So obviously, after the cutoff for as when we continue to recruit the Phase I study in monotherapy, both to test the weekly dosing, which we were doing, which we will report out on, but also to continue to recruit additional patients on monotherapy at the recommended Phase II dose of 2.5 mg per kg every 3 weeks. And we focused on enrolling patients that were closer to our strategy going forward in combination. So hopefully out of that data set, which will put out, we haven't even guided yet for this year, but we'll do that as soon we're able to be specific. You should see additional monotherapy data and inactivity was going to be ZW49 in some of those patient populations where it would have been nice to see more before the ESMO cut off. And obviously, that leaves a little bit of our thinking going forward into looking at the combination strategy of just making sure we've got reasonable contribution, single-activity and the highest quality patients we can track in the [ianduble]...

是的，史蒂夫。這是準確的。很明顯，在我們繼續招募單藥治療 I 期研究的截止日期之後，既要測試我們正在做的每週給藥，我們也會報告，但也要繼續招募更多的單藥治療患者建議的 II 期劑量為每 3 週 2.5 mg/kg。我們專注於招募更接近我們未來發展戰略的患者。因此，希望從將要發布的數據集中，我們今年甚至還沒有提供指導，但我們會盡快做到這一點。您應該會看到更多的單一療法數據，並且在某些患者群體中不活動將是 ZW49，在 ESMO 中斷之前看到更多這些患者群體會很高興。顯然，這讓我們有一點思考可以繼續研究組合策略，即確保我們有合理的貢獻、單一活動和我們可以在 [ianduble] 中追踪的最高質量的患者......

Great. And will the Phase IIs be randomized, -- like I assume there'll be a dose escalation single arm initially, but then will be each turn into randomized trials.

偉大的。 II 期是否會隨機化——就像我假設最初會有單臂劑量遞增，但隨後每組都會變成隨機試驗。

Yes. We haven't given any specific thought about the core design. We won't do that in all its up on control.gov. Obviously, we're trying to go quickly, recruit the right patients in the right cohort to answer the question as to whether we have a value proposition with [ZaniZov] or not. And if we do, then be able to move really quickly into a registration pathway. And so there's a lot of factors we're considering how we're designing and executing these studies. So I think once on control start out, we're happy to answer those questions about why we designed it the way we did.

是的。我們還沒有對核心設計給出任何具體的想法。我們不會在 control.gov 上這樣做。顯然，我們正試圖快速行動，在合適的隊列中招募合適的患者來回答我們是否對 [ZaniZov] 有價值主張的問題。如果我們這樣做了，那麼就能夠真正快速地進入註冊途徑。因此，我們正在考慮如何設計和執行這些研究的很多因素。所以我認為一旦控制開始，我們很樂意回答關於為什麼我們按照我們的方式設計它的問題。

I'm showing no additional questions in the queue at this time. I'd like to turn the conference back over to management for any closing remarks.

我目前沒有在隊列中顯示其他問題。我想將會議轉回管理層聽取任何閉幕詞。

That's great. Well, thank you for your attention today and for your questions. We have here a lot of progress last year in Zymeworks. And I think for 2023, we've got really good momentum across the business. We're really looking forward to having a great AACR coming up in April, and those abstracts will be available publicly soon. We're very [proud] to have 11 different abstracts accepted for this meeting. Last year, we had 0. So we're really looking forward to having a fulsome disclosure of the products and platforms in the early R&D group in the 5x5 strategy that we have and talking more about that. We look forward to doing that very quickly. So thank you for your time and attention to look forward to reporting more progress as we move forward through the year.

那太棒了。好的，感謝您今天的關注和提問。去年我們在 Zymeworks 方面取得了很大進展。我認為到 2023 年，我們整個行業的發展勢頭非常好。我們真的很期待在 4 月份有一個很棒的 AACR，這些摘要將很快公開。我們非常 [自豪] 本次會議接受了 11 份不同的摘要。去年，我們有 0。因此，我們真的很期待在我們擁有的 5x5 戰略中對早期研發團隊的產品和平台進行全面披露，並對此進行更多討論。我們期待很快做到這一點。因此，感謝您抽出時間和關注我們，期待在我們前進的過程中報告更多進展。

Ladies and gentlemen, thank you for participating in today's conference. This concludes the program. You may now disconnect. Everyone, have a wonderful day.

女士們，先生們，感謝你們參加今天的會議。程序到此結束。您現在可以斷開連接。每個人，祝你有美好的一天。