Mersana Therapeutics Inc (MRSN) 2024 Q2 法說會逐字稿

Good morning and welcome to Mersana Therapeutics second-quarter 2024 conference call and webcast. (Operator Instructions) Please note this call is being recorded. I would now like to turn the call over to Jason Fredette, Senior Vice President, Investor Relations and Corporate Communications.

早安，歡迎來到 Mersana Therapeutics 2024 年第二季電話會議和網路廣播。（操作員說明）請注意此通話正在錄音。我現在想將電話轉給投資者關係和企業傳播部高級副總裁傑森·弗雷戴特 (Jason Fredette)。

Thank you, operator, and good morning, everyone. Before we begin, please note that this call will contain forward-looking statements within the meaning of federal securities laws. These statements may include but are not limited to those related to our platforms, product candidates, business strategy, clinical trial execution and data, business development efforts and cash runway.

謝謝接線員，大家早安。在我們開始之前，請注意，本次電話會議將包含聯邦證券法含義內的前瞻性陳述。這些聲明可能包括但不限於與我們的平台、候選產品、業務策略、臨床試驗執行和數據、業務開發工作和現金跑道相關的聲明。

Each of these forward-looking statements are subject to risks and uncertainties that could cause actual results to differ materially from those projected in such statements. These risks and uncertainties are discussed in our quarterly report on Form 10-Q filed with the Securities and Exchange Commission on May 9, 2024 and in subsequent SEC filings.

這些前瞻性陳述均面臨風險和不確定性，可能導致實際結果與此類陳述中預測的結果有重大差異。這些風險和不確定性在我們於 2024 年 5 月 9 日向美國證券交易委員會提交的 10-Q 表格季度報告以及隨後向 SEC 提交的文件中進行了討論。

Our filings are available at sec.gov and on our website, mersana.com. Except as required by law, we assume no obligation to update forward-looking statements publicly even if new information becomes available in the future.

我們的備案文件可在 sec.gov 和我們的網站 mersana.com 上取得。除法律要求外，即使將來出現新訊息，我們也不承擔公開更新前瞻性聲明的義務。

On today's call, we have Mersana's President and Chief Executive Officer, Dr. Marty Huber; and our Chief Operating Officer and Chief Financial Officer, Brian DeSchuytner.

出席今天的電話會議的有 Mersana 總裁兼執行長 Marty Huber 博士；以及我們的營運長兼財務長 Brian DeSchuytner。

With that, let me turn the call over to Marty to begin our discussion.

接下來，讓我將電話轉給馬蒂，開始我們的討論。

Thank you, Jason, and good morning, everyone. The second quarter of 2024 was a time of continued progress at Mersana as we advanced dose escalation in Phase 1 clinical trials of XMT-1660, our lead Dolasynthen ADC candidate and XMT-2056, our lead Immunosynthen ADC candidate.

謝謝傑森，大家早安。2024 年第二季是Mersana 持續進展的時期，我們在XMT-1660（我們的主要Dolasynthen ADC 候選藥物）和XMT-2056（我們的主要Immunosynthen ADC 候選藥物）的1 期臨床試驗中推進了劑量遞增。

At the same time, we made further progress in our collaborations while also benefiting from our efforts to reduce our operating expenses last year. We believe these collective accomplishments have put us in a strong position as we approach our initial clinical data readout for XMT-1660, which is planned for the second half of this year.

同時，我們的合作取得了進一步的進展，同時也受益於去年我們削減營運費用的努力。我們相信，當我們計劃在今年下半年公佈 XMT-1660 的初步臨床數據時，這些集體成就使我們處於有利地位。

Let's begin with that program, XMT-1660 is an ADC we developed using Dolasynthen, our next generation cytotoxic ADC platform. This candidate targets B7-H4, a cell surface protein within the B7 family that can suppress anti-tumor immunity and can serve as a negative prognostic indicator for multiple tumor types.

讓我們從這個程式開始，XMT-1660 是我們使用 Dolasynthen（我們的下一代細胞毒性 ADC 平台）開發的 ADC。該候選藥物針對 B7-H4，這是 B7 家族中的一種細胞表面蛋白，可抑制抗腫瘤免疫，並可作為多種腫瘤類型的負面預後指標。

In the dose-escalation portion of our ongoing Phase 1 clinical trial, we are enrolling patients with tumor types that most commonly expressed high levels of B7-H4. These include patients with recurrent triple negative and hormone receptor-positive breast cancers, as well as endometrial and ovarian cancers, all areas with high unmet medical need.

在我們正在進行的 1 期臨床試驗的劑量遞增部分中，我們正在招募最常表達高水平 B7-H4 的腫瘤類型的患者。其中包括患有復發性三陰性和荷爾蒙受體陽性乳癌的患者，以及子宮內膜癌和卵巢癌患者，這些領域的醫療需求都未被滿足。

For instance, as many know, Trodelvy and or in HER2 are being used to treat the vast majority of recurrent triple negative breast cancer patients in the US today. The emerging clinical data continue to suggest that patients can develop resistance to ADCs with Topo-1 inhibitor payloads.

例如，眾所周知，Trodelvy 和/或 HER2 正在用於治療當今美國絕大多數復發性三陰性乳癌患者。新出現的臨床數據繼續表明，患者可能會對含有 Topo-1 抑制劑有效負載的 ADC 產生抗藥性。

As a result, we are hearing an increasing call among treating physicians for new ADCs with alternative payloads that aren't subject to Topo-1 or PGP efflux resistance mechanisms. XMT-1660 fits this profile, and we are enrolling many patients who have received a prior Topo-1 ADC in our trial.

因此，我們聽到治療醫生越來越多地呼籲採用不受 Topo-1 或 PGP 外排抵抗機制影響的替代有效負載的新型 ADC。XMT-1660 符合這項特點，我們正在招募許多先前接受過 Topo-1 ADC 的患者參加我們的試驗。

Dose escalation remains ongoing, and we still have not established a maximum tolerated dose. In fact, we are currently at a dose of 80 milligrams per meter squared in escalation. This is well beyond the dose levels, we were able to reach clinically with any of our prior ADCs.

劑量遞增仍在持續，我們仍未確定最大耐受劑量。事實上，我們目前的劑量正在逐步升級為每平方公尺 80 毫克。這遠遠超出了我們之前任何 ADC 能夠達到的臨床劑量水平。

We believe our ability to continue to dose escalate can be attributed to two factors. The first is Dolasynthen’s ability to reduce toxicities commonly associated with other ADC platforms like neutropenia, neuropathy and ocular toxicity, as well as those that were seen with our first-generation platform Dolaflexin.

我們相信我們繼續增加劑量的能力可歸因於兩個因素。首先是 Dolasynthen 能夠減少與其他 ADC 平台常見的毒性，如中性粒細胞減少症、神經病變和眼毒性，以及我們的第一代平台 Dolaflexin 中出現的毒性。

And the second factor is that based on data that has been reported to date, there does not appear to be an obvious on-target liability with B7-H4. In parallel with our dose escalation work, which includes the enrollment of backfill cohorts, we are also proactively exploring different dosing schedules with XMT-1660 with the aim to optimize efficacy and safety. This has included every four weeks as well as more frequent dosing regimens.

第二個因素是，根據迄今為止報告的數據，B7-H4 似乎不存在明顯的瞄準目標責任。在我們的劑量遞增工作（包括回填隊列的招募）的同時，我們也正在積極探索 XMT-1660 的不同給藥方案，以優化療效和安全性。這包括每四個星期一次以及更頻繁的給藥方案。

At the same time, we also are progressing our biomarker strategy in preparation for expansion and potential later stages of development. All of this work is aimed at building a robust dataset that can inform important strategic decisions as we seek to position XMT-1660 as a potential best-in-class asset, one that we believe may have the opportunity to serve both as a monotherapy and in combination with standard of care that may be inaccessible for the other B7-H4 ADCs in development.

同時，我們也在推動我們的生物標記策略，為擴張和潛在的後期發展做好準備。所有這些工作的目的都是建立一個強大的數據集，可以為重要的戰略決策提供信息，因為我們尋求將XMT-1660 定位為潛在的同類最佳資產，我們相信它可能有機會既作為單一療法又作為一種藥物。

We continue to expect that we will be in a position to announce our initial clinical data and initiate expansion in the second half of this year. This readout will include safety, tolerability, efficacy and biomarker data.

我們仍然預計我們將能夠在今年下半年公佈我們的初步臨床數據並開始擴展。該讀數將包括安全性、耐受性、有效性和生物標記數據。

Now let's turn to Immunosynthen and XMT-2056. Immunosynthen is an innate immune stimulating ADC platform. Last month, we were pleased to publish preclinical data in Nature Communications regarding some of the key mechanistic underpinnings of our approach to activate STING in a targeted manner using an ADC.

現在讓我們轉向Immunosynthen 和XMT-2056。Immunosynthen 是一種先天免疫刺激 ADC 平台。上個月，我們很高興在《Nature Communications》上發布了臨床前數據，涉及我們使用 ADC 有針對性地激活 STING 的方法的一些關鍵機制基礎。

This included in vitro and in vivo data, demonstrating a one-two punch consisting of target dependent STING activation in both tumor cells and tumor resident immune cells. The data also showed increased antitumor efficacy and reduced serum cytokine elevations in comparison to a free STING agonist.

這包括體外和體內數據，證明了腫瘤細胞和腫瘤駐留免疫細胞中由目標依賴性 STING 活化組成的一對二衝擊。數據也顯示，與遊離 STING 激動劑相比，抗腫瘤功效增強，血清細胞激素升高降低。

XMT-2056 as our lead STING agonist ADC candidate that we developed using Immunosynthen. It targets a novel HER2 epitopes that we believe could enable it to not only be an effective monotherapy, but also could allow for eventual combinations with a range of other agents, including other HER2 targeted therapies.

XMT-2056是我們使用Immunosynthen開發的主要STING激動劑ADC候選藥物。它針對一種新的 HER2 表位，我們相信該表位不僅可以使其成為有效的單一療法，而且還可以最終與一系列其他藥物（包括其他 HER2 標靶療法）聯合使用。

The dose escalation portion of our Phase 1 trial is advancing and is enrolling patients with HER2-positive tumors, including breast, gastric, colorectal and non-small cell lung cancer. We expect to make good progress in escalation this year.

我們第一期試驗的劑量遞增部分正在推進，正在招募 HER2 陽性腫瘤患者，包括乳癌、胃癌、大腸癌和非小細胞肺癌。我們預計今年升級工作將取得良好進展。

And finally, I'm pleased to report that we continue to advance our discovery collaborations with Johnson & Johnson and Merck KGaA. In fact, we have been performing CMC activities to support J&J and earlier this month, we earned another milestone this one for $8 million related to that Dolasynthen collaboration. Payment of this milestone is due in the third quarter of 2024.

最後，我很高興地向大家報告，我們將繼續推動與強生公司和默克公司的發現合作。事實上，我們一直在進行 CMC 活動來支持強生，本月早些時候，我們因與 Dolasynthen 的合作而獲得了另一個里程碑，即 800 萬美元。這一里程碑的付款將於 2024 年第三季支付。

Now, let's turn things over to Brian for our Q2 financial update.

現在，讓我們將第二季的財務更新交給布萊恩。

Thank you, Marty. Let's get into the financial highlights for the second quarter of 2024, starting with our balance sheet. We ended the second quarter with $162.7 million in cash, cash equivalents and marketable securities. We continue to expect our available funds will support our operating plan commitments into 2026.

謝謝你，馬蒂。讓我們從資產負債表開始，了解 2024 年第二季的財務亮點。第二季末，我們擁有 1.627 億美元的現金、現金等價物和有價證券。我們繼續預計我們的可用資金將支持我們到 2026 年的營運計劃承諾。

Please note that our cash runway guidance does not assume any future milestone payments that we may earn from our current collaborations or proceeds that we may realize from future collaborations. Net cash used in operating activities for the second quarter of 2024 was $21.8 million, down significantly from the $61.8 million in net cash used during the year ago quarter. This decrease primarily reflects the portfolio reprioritization efforts and OpEx reductions we implemented in the second half of 2023.

請注意，我們的現金跑道指導不假設我們可能從當前合作中賺取的任何未來里程碑付款或我們可能從未來合作中實現的收益。2024 年第二季經營活動使用的淨現金為 2,180 萬美元，較上年同期的 6,180 萬美元淨現金大幅下降。這一下降主要反映了我們在 2023 年下半年實施的投資組合優先順序調整工作和營運支出削減。

Turning to our income statement, collaboration revenue for the second quarter of 2024 was $2.3 million compared to $10.7 million for the same period of 2023. The year over year change is primarily related to reduced collaboration revenue recognized under our Johnson & Johnson and Merck KGaA collaboration agreements.

轉向我們的損益表，2024 年第二季的協作收入為 230 萬美元，而 2023 年同期為 1,070 萬美元。年比變化主要與強生公司和默克公司合作協議下確認的合作收入減少有關。

Research and development expenses for the second quarter of 2024 declined significantly to $17.2 million compared to $49 million for the same period in 2023. For the most recent quarter, approximately $2.4 million of this spending was related to non-cash stock-based compensation.

2024 年第二季的研發費用大幅下降至 1,720 萬美元，而 2023 年同期為 4,900 萬美元。在最近一個季度，該支出中約 240 萬美元與非現金股票薪酬相關。

The year-over-year decline in R&D expenses was primarily related to reduced costs associated with manufacturing and clinical activities for our discontinued ADC UpRi and reduced employee compensation expense following the restructuring we completed in 2023.

研發費用的年減主要與我們已停產的 ADC UpRi 的製造和臨床活動相關成本的降低以及我們在 2023 年完成重組後員工薪酬費用的減少有關。

General and administrative expenses for the second quarter of 2024 declined significantly to $10.5 million compared to $18.2 million during the same period in 2023. Approximately $2 million in non-cash stock-based compensation expenses were included in G&A for the most recent quarter.

2024 年第二季的一般及管理費用大幅下降至 1,050 萬美元，而 2023 年同期為 1,820 萬美元。最近一個季度的一般管理費用中包含約 200 萬美元的非現金股票補償費用。

The year-over-year decline in G&A was primarily related to reduced consulting and professional services fees and reduced employee compensation expenses following our restructuring. And finally, Mersana's net loss for the second quarter of 2024 was $24.3 million compared to a net loss of $54.3 million for the same period in 2023.

一般行政費用較去年同期下降主要與重組後諮詢和專業服務費用的減少以及員工薪資費用的減少有關。最後，Mersana 2024 年第二季的淨虧損為 2,430 萬美元，而 2023 年同期的淨虧損為 5,430 萬美元。

That concludes our business update. Operator, would you please open the call for questions from the audience?

我們的業務更新到此結束。接線生，請您打開觀眾提問電話好嗎？

(Operator Instructions) Tara Bancroft, TD Cowen.

（操作員說明）Tara Bancroft，TD Cowen。

Hi, good morning, everyone. So I was hoping you could give us maybe a qualitative measure of how patients are doing in the trial. I mean, you previously noted that responses are being observed, but have you observed more or deepening since then? And for safety, other than no MTD being reached, are you happy with the level of grade three events that you're seeing? Thanks.

嗨，大家早安。所以我希望你能給我們一個關於病人在試驗中表現的定性衡量標準。我的意思是，您之前註意到正在觀察反應，但從那時起您是否觀察到更多或加深？為了安全起見，除了沒有達到 MTD 之外，您對所看到的三級賽事的水平是否滿意？謝謝。

Thank you Tara. While we're not giving any details on the 1660 clinical data, I think there are a couple of points is, one, we are at 80 milligrams per meter squared, and this is a dose that equates to roughly 2.2 milligrams per kilogram, which is much higher than we previously gone to the platform.

謝謝你塔拉。雖然我們沒有提供 1660 份臨床數據的任何細節，但我認為有幾點是，第一，我們的劑量為每平方米 80 毫克，這個劑量大約相當於每公斤 2.2 毫克，比我們之前去的平台要高很多。

So, while we're not talking about details of grade three, et cetera, events, we are comfortable that we're able to escalate to this dose range. We're not getting into any details of the responses at this point in time or that information will be included in our second half data disclosure.

因此，雖然我們不討論三年級等事件的細節，但我們很高興能夠升級到這個劑量範圍。目前我們還沒有透露任何回應的細節，或資訊將包含在我們下半年的數據揭露中。

Okay, thanks so much.

好的，非常感謝。

Jonathan Chang, Leerink Partners.

喬納森·張 (Jonathan Chang)，Leerink 合夥人。

Good morning. Thanks for taking my questions. First question on 1660, can you discuss the progress you're making on the biomarker front and how much and what biomarker data we could see in the second half disclosure?

早安.感謝您回答我的問題。關於1660的第一個問題，您能否討論一下您在生物標誌物方面取得的進展以及我們在下半年披露中可以看到多少和哪些生物標誌物數據？

And second question, can you provide any more granularity on when and how you plan to disclose the initial 1660 clinical data. Thank you.

第二個問題，您能否更詳細地說明您計劃何時以及如何披露最初的 1660 項臨床數據。謝謝。

I'm going to cover the biomarker answer and then I'll turn it over to Jason regarding the future disclosure. With regards to biomarker just to remind everybody, we selected patient populations that was the tumor types, triple-negative breast cancer, hormone receptor-positive breast cancer, endometrial and ovarian, that all have higher levels of expression of B7-H4.

我將介紹生物標誌物的答案，然後將其轉交給 Jason 關於未來的披露。關於生物標記，提醒大家一下，我們選擇的患者族群是B7-H4表達量較高的腫瘤類型，三陰性乳癌，荷爾蒙受體陽性乳癌，子宮內膜癌和卵巢癌。

However, within those populations, we are not requiring a patient to be biomarker-positive to be enrolled. In other words, we're enrolling all comers across that. We are capturing tissue, which we are analyzing retrospectively for the expression of B7-H4.

然而，在這些人群中，我們並不要求患者生物標記呈陽性才能入組。換句話說，我們正在招募所有遇到這種情況的人。我們正在捕獲組織，並對其 B7-H4 的表達進行回顧性分析。

So what our plan would be in the initial data disclosure is to provide some information that would allow us -- we'll share with you kind of our thinking on do we believe a biomarker will be necessary for patient selection going forward or not. As of today, we have not made that decision, but we will continue to gather data on biomarker negative and positive to inform that decision.

因此，我們在最初的數據披露中的計劃是提供一些信息，使我們能夠——我們將與您分享我們的想法，即我們是否相信生物標誌物對於未來的患者選擇是必要的。截至今天，我們尚未做出該決定，但我們將繼續收集有關生物標記陰性和陽性的數據，以便為該決定提供資訊。

And Jonathan, on additional color, we really don't have additional color to share at this stage. We're keeping the guidance at second half. If that could be a company event or it could be a medical congress at this stage, we haven't defined that.

喬納森，關於額外的顏色，我們現階段確實沒有額外的顏色可以分享。我們將維持下半年的指導。如果這可能是公司活動或現階段的醫學大會，我們還沒有定義。

Got it. If I could just maybe fill in one more follow-up question here. Also on 1660, just to clarify, have you already committed to this expansion portion of the study. I guess what do you need to see and address before initiating the expansion portion of the study. Thanks You.

知道了。如果我能在這裡再補充一個後續問題就好了。另外，在 1660 年，我想澄清一下，您是否已經致力於研究的擴展部分。我想在開始研究的擴展部分之前，您需要了解和解決什麼問題。感謝您。

We have built the expansion cohorts into the existing protocol, so that work has all been done. The step we're left is the identification of a recommended Phase 2 at least one recommended Phase 2 dose to take forward into the expansion. And as we have not yet defined at MTD, we are not at ready to declare a recommended Phase 2 dose at this point in time.

我們已將擴展隊列建置到現有協定中，因此所有工作都已完成。我們剩下的步驟是確定建議的第 2 階段至少一種建議的第 2 階段劑量，以推進擴展。由於我們尚未在 MTD 上進行定義，因此我們目前尚未準備好宣佈建議的 2 期劑量。

Understood. Thank you.

明白了。謝謝。

Ashiq Mubarak, Citi.

阿希克·穆巴拉克，花旗銀行。

Hi, guys. Thanks for taking my question. In the press release, you called out the 80 mg dose every four weeks, which seems to be less frequent dosing compared with some of the data we've seen from your peers in the B7-H4 space.

嗨，大家好。感謝您提出我的問題。在新聞稿中，您提出每四周一次 80 毫克的劑量，與我們從 B7-H4 領域的同行看到的一些數據相比，這似乎不太頻繁。

I'm just curious how important you think dosing frequency could be as a potential differentiator. And on a similar point, I think in the past, you've talked about the need to sort of work through the exposure optimization. I'm wondering if you could share any color on where you are in that process and how close you are to figuring out optimal exposure? Thank you.

我只是好奇你認為給藥頻率作為一個潛在的差異化因素有多重要。在類似的一點上，我認為您過去曾談到需要透過曝光優化來進行工作。我想知道你是否可以分享一下你在這個過程中所處的位置以及你距離找出最佳曝光有多近？謝謝。

Thank you for the question. First of all, we have spoken about the every four weeks. And one of the reasons we're able to explore the every four week schedule is because our molecule and we have shared preclinical data shows an extended half-life compared to other molecules, we have antibody-like half-life for our Dolasynthen ADCs.

謝謝你的提問。首先，我們談到了每四個星期一次。我們能夠探索每四周一次的時間表的原因之一是因為我們的分子和我們共享的臨床前數據顯示與其他分子相比半衰期更長，我們的 Dolasynthen ADC 具有類似抗體的半衰期。

So when you have that long half-life, that allows you to explore these longer schedules, which we do think could be a potential advantage in the clinic. But at the same time, it may be more effective to have more frequent dosing, to decreased C-max relative to AUC and maintain more exposure over time.

因此，當你有那麼長的半衰期時，你就可以探索這些更長的時間表，我們確實認為這可能是臨床上的潛在優勢。但同時，更頻繁地給藥、相對於 AUC 降低 C-max 並隨著時間的推移保持更多的暴露可能更有效。

That is an unknown -- we have a question we don't have an answer for and that's one of the reasons we made the decision to proactively explore the every four week schedule dose escalation in parallel to more frequent dose -- a more frequent schedules.

這是一個未知數——我們有一個沒有答案的問題，這就是我們決定主動探索每四周一次的劑量遞增與更頻繁的劑量並行的原因之一——更頻繁的時間表。

So we are generating data on both every four week as well as shorter intervals. And we should have that data as part of the second half presentation, which would then allow us as part of the recommended Phase 2 dose, to define not only what that doses, but also discuss the appropriate schedule.

因此，我們每四個星期以及更短的時間間隔產生資料。我們應該將這些數據作為下半年演示的一部分，這將使我們能夠作為建議的第二階段劑量的一部分，不僅可以定義劑量，還可以討論適當的時間表。

Okay. Got it. And if I could ask one follow-up. I think you have alluded in the past to maybe needing to establish a Phase 2 dose before, sharing the data with us is it also necessary to establish an MTD as per the primary endpoint of the study before you show the data, or is that not necessary? Thank you.

好的。知道了。如果我可以問一個後續問題。我想您過去曾提到過，之前可能需要確定 2 期劑量，與我們分享數據是否也有必要在您展示數據之前根據研究的主要終點建立 MTD，或者不是必要的？謝謝。

An MTD is not critical. We don't necessarily have to get to an MTD. I think we wanted before we declare a recommended Phase 2 dose, though, is have some understanding of kind of where is the upper bound that you can get to, whether that's a formal protocol specified MTD or just a general observation of you're starting to see payload effects.

MTD 並不重要。我們不一定非要達到 MTD。不過，我認為在宣佈建議的第 2 階段劑量之前，我們希望對您可以達到的上限有一些了解，無論這是正式方案指定的 MTD 還是只是對您開始的一般觀察查看有效負載效果。

So I think what -- we want to be a little careful saying we have to see an MTD, but I think given the fact that ADCs historically have had relatively narrow therapeutic indices, I think we do want to see kind of where is that upper bound before we make a call on which dose we're taking to expansion.

所以我認為——我們要謹慎地說我們必須看到 MTD，但我認為考慮到 ADC 歷來具有相對狹窄的治療指數，我認為我們確實希望看到上限在哪裡在我們決定要採取何種劑量的擴張之前，我們必須先確定這一點。

Got it. Thank you very much.

知道了。非常感謝。

Michael Schmidt, Guggenheim.

邁克爾·施密特，古根漢。

Hey, good morning. Thanks for taking my questions. I was wondering if you could comment a bit more on whether you have observed a dose response in the every four week dosing cohort so far. I know you've commented on seeing responses earlier than the 80 milligrams dose. So just curious, and then also what magnitude of increase in dose exposure one would expect perhaps with a more frequent dosing schedule?

嘿，早安。感謝您回答我的問題。我想知道您是否可以多評論一下到目前為止您是否在每四周的給藥隊列中觀察到劑量反應。我知道您曾評論過在 80 毫克劑量之前就看到了反應。所以只是好奇，那麼如果採用更頻繁的給藥方案，人們預期劑量暴露的增加幅度會是多少？

Thank you, Michael. We're not sharing any further color on exposure response relationships. I think we did disclose that, we had responses at doses previously before we got to 80 milligrams dose. So I think what we -- we can be explicit that we have seen responses at the lower -- doses lower than 80, that was in our previous disclosure. And with regards to exposure response relationships that would be premature at this point in time and that will be part of the second half data disclosure.

謝謝你，麥可。我們不會分享任何有關暴露反應關係的更多資訊。我認為我們確實披露了這一點，在我們達到 80 毫克劑量之前，我們之前的劑量就有反應。所以我認為我們——我們可以明確表示，我們已經看到了低於 80 劑量的反應，這是我們之前披露的。至於暴露反應關係，目前還為時過早，這將是下半年數據揭露的一部分。

The second part of your question was?

你問題的第二部分是？

I think though, that on that topic. And the other question I had is as we monitor forthcoming data from other companies pursuing B7-H4, for example, AstraZeneca, who will have some data at ESMO, yeah, I'm just curious how we should (inaudible - microphone inaccessible)

但我認為，關於這個主題。我的另一個問題是，當我們監控其他追求 B7-H4 的公司即將發布的數據時，例如阿斯特捷利康，他們將在 ESMO 獲得一些數據，是的，我只是好奇我們應該如何（聽不清楚 - 麥克風無法存取）

Yeah, Michael, you're coming in and out. Are you asking for some speculation about AZ?

是的，邁克爾，你進來又出去。您是否想對 AZ 進行一些猜測？

Yeah. I'm just curious as we kind of look forward to ESMO, where they have an update on their data, how investors should interpret their results and how it may read through your program, if anything on that?

是的。我只是好奇，因為我們有點期待 ESMO，他們會更新他們的數據，投資者應該如何解釋他們的結果，以及它如何閱讀你的程序，如果有的話？

Sure, Michael, maybe I can handle that. From a safety and tolerability perspective, we would expect to see the typical Topo-1 platform toxicities, those include things like myelosuppression. I think that that's relevant because it speaks to which combination opportunities may be more or less challenging for an asset like that.

當然，邁克爾，也許我能處理好。從安全性和耐受性的角度來看，我們預計會看到典型的 Topo-1 平台毒性，其中包括骨髓抑制等。我認為這是相關的，因為它說明了對於此類資產來說，哪些合併機會或多或少具有挑戰性。

From an efficacy standpoint, to the extent that AZ shows, responses in breast cancer, we frankly believe the question in this space, we'll be how many of those responses were generated in patients who have been previously treated with a prior Topo-1 ADCs.

從功效的角度來看，就 AZ 顯示的乳癌反應而言，我們坦率地相信這個領域的問題，我們將了解有多少這些反應是在先前接受過 Topo-1 治療的患者中產生的ADC。

AZ has been enrolling this trial globally, including in potentially locations where patients are more likely to be naïve to Topo-1 ADCs. Here in the US, the vast majority of current triple-negative breast cancer patients are being treated with Trodelvy and or an HER2.

AZ 一直在全球招募這項試驗，包括在患者更有可能未接觸過 Topo-1 ADC 的潛在地區。在美國，目前絕大多數三陰性乳癌患者正在接受 Trodelvy 和/或 HER2 治療。

Emerging data, and we've spoken about this before, continue to suggest that patients can develop resistance to ADCs with those Topo-1 payloads. As a result, as Marty noted in the opening remarks, there's an increase in call from physicians to find ADCs with new sort of athigonoal payloads that aren't subject to the Topo-1 resistance mechanisms or PGP pump.

我們之前已經討論過這一點，新出現的數據繼續表明，患者可能會對使用這些 Topo-1 有效負載的 ADC 產生抗藥性。因此，正如 Marty 在開場白中指出的那樣，醫生越來越多地呼籲尋找具有不受 Topo-1 抗藥性機製或 PGP 泵影響的新型 athigonoal 有效負載的 ADC。

So I guess the key question that people should be looking for is, what are those prior treatments and the demographics of those patients?

所以我想人們應該尋找的關鍵問題是，這些患者的先前治療方法和人口統計數據是什麼？

Great. Thank you so much.

偉大的。太感謝了。

(Operator Instructions) Charles Zhu, LifeSci.

（操作員說明） Charles Zhu，LifeSci。

Good morning, everyone, and thanks for taking the questions. Given that your XMT-1660 protocol allows for pretty sizable backfilling, how are you thinking or have been thinking about prioritizing enrollment towards further advancing dose, escalation slash exploration versus collecting more data at any given backfill cohort? And has this thinking evolved as you've continued to advance further into clinically relevant doses and schedules? Thank you.

大家早安，感謝您提出問題。鑑於您的 XMT-1660 協議允許相當大的回填，您如何考慮或一直在考慮優先考慮入組以進一步提高劑量、逐步升級探索，而不是在任何給定的回填隊列中收集更多數據？隨著您繼續深入研究臨床相關劑量和時間表，這種想法是否有所發展？謝謝。

Well, first of all, yeah, the protocol just to provide you for everybody, allows up to 12 patients at a given dose as well as at a given indication. So it does give us a lot of flexibility to get significant patient numbers at a given dose and tumor type.

嗯，首先，是的，該方案只是為每個人提供，允許最多 12 名患者接受給定的劑量和給定的適應症。因此，它確實為我們提供了很大的靈活性，可以在給定劑量和腫瘤類型下獲得大量患者。

How do we think about that, I think we've probably been fairly explicit that TNBC is probably the one we spend the most time talking about as it's the area of highest unmet medical need. So I do think what we would look toward in this data set is, how do -- one were getting TNBC patients, high unmet medical need, B7-H4 is fairly frequent there.

我們如何看待這一點，我認為我們可能已經相當明確地表示，TNBC 可能是我們花最多時間討論的一個，因為它是醫療需求未滿足程度最高的領域。因此，我確實認為我們在這個數據集中關注的是，如何處理 TNBC 患者，未滿足的醫療需求很高，B7-H4 在那裡相當頻繁。

A second scenario, as Brian alluded to in the differentiation from the others looking at a US based population where most TNBC patients will have seen Trodelvy and or in HER2 is a great place to explore the hypothesis that our ADC with its novel scaffolding or payload, will have an opportunity to show activity in settings where Topo payloads are unlikely to be effective.

第二種情況，正如Brian 在與其他研究美國人群的區別中提到的那樣，大多數TNBC 患者都會在HER2 中看到Trodelvy 和/或在HER2 中，這是一個很好的地方來探索我們的ADC 及其新穎的支架或有效負載的假設，將有機會展示 Topo 有效負載不太可能有效的環境中的活動。

So I think for us the -- while we're not giving details of exactly what patient types the way the protocol design we can enroll, expand, backfill that with TNBC or other Topo types and really tried to answer that question of what's the activity of this kind of post Topo environment? So that would be one of the datasets that we should -- or one of the data points we should be able to include in our second half disclosure.

因此，我認為對我們來說，雖然我們沒有按照方案設計的方式詳細說明患者類型，但我們可以用 TNBC 或其他拓撲類型進行註冊、擴展、回填，並真正嘗試回答活動是什麼的問題這種後拓撲環境？因此，這將是我們應該包含的資料集之一，或者我們應該能夠包含在下半年揭露中的資料點之一。

Got it. And maybe if I could just ask one follow up on that. Just given the FDA Project Optimus environment and what sounds like your intention to take one go forward dose as opposed to more than one, I guess then, -- is it fair to assume then that you would have backfilled across or backfilled enough patients at each given dose level to have made that determination by end of this year? Thank you.

知道了。也許我可以問一個後續問題。考慮到 FDA Optimus 計畫的環境，以及聽起來您打算服用一劑前進劑量而不是一劑以上，我想，那麼假設您會在每次回填或回填足夠的患者是否公平？年底前做出了決定？謝謝。

I think one of the things we're careful or we need, least one recommended Phase 2 dose and we will be careful, it could be two. The way expansion is written in the protocol, it gives us the flexibility to take one or two. We do recognize that with the way Project Optimus is rolling out at some point in time, we will formally -- we will likely formally have to study two doses.

我認為我們要小心或我們需要的一件事是，至少一劑建議的第二階段劑量，我們會小心，可能是兩劑。擴展在協議中的編寫方式使我們可以靈活地採用一兩種。我們確實認識到，隨著擎天柱計劃在某個時間點的推出，我們將正式上——我們可能必須正式研究兩種劑量。

But if you if you look at the precedents here and some of the guidance for the agency having meaningful backfill patients at multiple, doses does go in the direction of health answering questions for Project Optimus. So hopefully, it'll minimize the number of doses we would have to take into the actual pivotal programs.

但如果你看看這裡的先例以及該機構對多個有意義的患者進行有意義的補充的一些指導，劑量確實符合健康的方向，回答了擎天柱計劃的問題。因此，希望它能最大限度地減少我們在實際關鍵計劃中必須採用的劑量數量。

I mean, there are folks out there today who are taking three or four doses and schedules into large registration enabling or registration targeted programs. And we think there is an opportunity based on precedent to narrow it down. Are we going to study two doses in the pivotal? Potentially, but the more information we get out of these backfills at multiple doses, the better will inform that discussion with the agency.

我的意思是，今天有人正在將三到四劑劑量和時間表納入大型註冊啟用或註冊目標計劃中。我們認為有機會根據先例來縮小範圍。我們要研究關鍵的兩種劑量嗎？有可能，但我們從多次劑量的回填中獲得的資訊越多，就越能為與該機構的討論提供資訊。

Understood. Thanks for taking the questions.

明白了。感謝您提出問題。

Colleen Kusy, Baird.

科琳·庫西，貝爾德。

Thanks. Good morning, and thanks for taking our questions. On the upcoming 1660 readout, can we expect biomarker data from all patients enrolled in escalation backfill, and will that be a meaningful enough data set to determine an ORR in that biomarker positive subgroup? And then for the expansion cohorts that you plan to open the second half of this year, would you be looking to open one or multiple tumor-specific expansion cohorts?

謝謝。早安，感謝您提出我們的問題。在即將到來的 1660 讀數中，我們是否可以預期參加升級回填的所有患者的生物標誌物數據，這是否是一個足夠有意義的數據集來確定該生物標誌物陽性亞組的 ORR？那麼，對於您計劃在今年下半年開設的擴展隊列，您會考慮開設一個還是多個腫瘤特異性擴展隊列？

With regards to the biomarker, I mean, one of the challenges of a retrospective analysis is, since you don't require the patient to have a documented positive before they enroll, you will have samples that will be invaluable for the biomarker. So, it would be presumptuous for me to sit here and say we're going to have 100% of the data on that topic.

關於生物標記，我的意思是，回顧性分析的挑戰之一是，由於您不要求患者在入組前有陽性記錄，因此您將擁有對於生物標記來說非常寶貴的樣本。因此，如果我坐在這裡說我們將擁有該主題的 100% 數據，那就太自以為是了。

But what we -- and the second thing -- remember, these are backfills. This is not a full expansion. So, your confidence intervals around any point estimate, and by the way, this applies to the CGM dataset, as well as the dataset that they presented last year at ESMO, are going to be relatively wide. So, trying to say we have a definitive response rate determination out of a Phase 1 dose escalation, would be overreaching.

但我們——以及第二件事——記住，這些是回填。這不是一個完整的擴充。因此，圍繞任何點估計的置信區間，順便說一句，這適用於 CGM 資料集，以及他們去年在 ESMO 上展示的資料集，將相對較寬。因此，試圖說我們已經確定了第一階段劑量遞增的明確緩解率，這有些過分了。

However, I do think we should have sufficient patients to get a directional answer is, how do these data look in the greater universe of data out there? And two, is there some differentiation in biomarker positive versus negative? We may still need to carry into expansion and or for that matter, pivotal studies all comers based on the evolving data.

然而，我確實認為我們應該有足夠的患者來獲得定向答案，即這些數據在更大的數據宇宙中看起來如何？第二，生物標記陽性與陰性之間是否存在一些差異？我們可能仍然需要根據不斷變化的數據對所有參與者進行擴展和/或就此而言的關鍵研究。

One of the things I learned, back on the Keytruda experience, if you don't have a clear signal, you want to be really careful there. After less than 100 lung cancer patients, we had quite a clear signal that we were able to select out a subset. I think when we go back to our UpRi experience, the biomarker there didn't perform so well. And that ultimately in the pivotal study had a negative consequence on our ability to -- on the data.

回顧 Keytruda 的經歷，我學到的一件事是，如果你沒有明確的訊號，你要非常小心。在不到 100 名肺癌患者之後，我們有一個非常明確的信號，表明我們能夠選擇一個子集。我認為當我們回到 UpRi 的體驗時，那裡的生物標記物表現得不好。最終，在這項關鍵研究中，這對我們處理數據的能力產生了負面影響。

So, I think it really is a data driven decision based on not only the performance, I mean, the biology of a specific biomarker, how the drug performs, but also then the performance of the biomarker itself. So, there are a lot of questions that we want to answer based on data.

所以，我認為這確實是一個數據驅動的決策，不僅基於性能，我的意思是，特定生物標誌物的生物學、藥物的性能，而且還基於生物標誌物本身的性能。因此，我們想要根據數據來回答很多問題。

Great. That's helpful. Thank you. And then just on the expansion cords, if you had opened one or multiple in the second half.

偉大的。這很有幫助。謝謝。如果您在後半段打開了一條或多根擴展線，那麼就在擴展線上。

We have all four written in -- at least four written into the protocol. However, based - we'll probably make some decisions on which ones we prioritize based on the data from the Phase 1. We can flexibly either do them or stage them or however, and that'll be a data-driven decision at that point in time.

我們已將所有四個內容都寫入了協議中——至少有四個內容已寫入協議中。然而，我們可能會根據第一階段的數據來決定優先考慮哪些內容。我們可以靈活地執行它們或分階段執行它們，或者無論如何，這將是當時數據驅動的決策。

Great. That makes sense. Thanks for taking our questions.

偉大的。這是有道理的。感謝您回答我們的問題。

Brian Cheng, JPMorgan.

布萊恩鄭，摩根大通。

Hey guys. Hey Marty, thanks for taking our question this morning. Just want to follow up on your comment earlier. Do you need to reach MTD to declare the recommended Phase 2 dose and then move into expansion? And then secondly is related to your ongoing work around more frequent dosing, is that just a typical part of any development plan to satisfy perhaps some of the requirement by Project Optimus, or is that actively driven by your observation to date in the clinics? Thanks.

嘿夥計們。嘿，馬蒂，感謝您今天早上提出我們的問題。只是想在早些時候跟進您的評論。您是否需要達到 MTD 來宣佈建議的 2 期劑量，然後進行擴展？其次，與您正在進行的圍繞更頻繁給藥的工作有關，這是否只是任何開發計劃的典型部分，以滿足 Optimus 項目的某些要求，或者是由您迄今為止在診所的觀察積極推動的？謝謝。

With regards to the first question on MTD, I think what we want to say is, in a perfect world, we would actually define a formal MTD and know what that is before we pick a recommended Phase 2 dose. The one thing we'd like to highlight on, especially when we see these ADCs, is sometimes you can have toxicities that don't achieve the level of a formal protocol-specified MTD, but patients aren't able to stay on that dose for more than a couple of cycles.

關於 MTD 的第一個問題，我認為我們想說的是，在完美的世界中，我們實際上會定義一個正式的 MTD，並在選擇建議的 2 期劑量之前知道它是什麼。我們要強調的一件事是，尤其是當我們看到這些 ADC 時，有時可能會產生未達到正式方案規定的 MTD 水平的毒性，但患者無法堅持使用該劑量超過幾個週期。

And then you end up in this Project Optimus situation where late in your program, you get taken to a lower dose. So, part of it is we want to understand, we say, we want to make sure our recommended Phase 2 dose has an opportunity to be truly tolerable, which means the vast majority of patients can stay on that dose throughout their treatment cycle, but it may not be a formal MTD protocol. That's where I want to clarify. We do want to see where does toxicity become dose limiting.

然後你最終會陷入擎天計畫的情況，在你的計畫後期，你會接受較低的劑量。因此，部分原因是我們想了解，我們想確保我們建議的 2 期劑量有機會真正耐受，這意味著絕大多數患者可以在整個治療週期中保持該劑量，但它可能不是正式的 MTD 協議。這就是我想澄清的地方。我們確實想看看毒性在哪裡會受到劑量限制。

With regards to your second question, was the --

關於你的第二個問題，--

Was the more frequent --

是比較頻繁的--

Frequent, yes. If you look at data on ADCs, and we looked at data from the CGM platform with the VCM MAE, there's this observation that certain toxicities tend to be C-max related. We made the decision with the initial delay that we announced in Q2, that instead of doing a sequential, see how high we can go with an every three or four week schedule, and then at that point, going back and seeing, could we increase exposure by doing a more frequent dosing, we made the decision to explore in parallel.

經常，是的。如果您查看 ADC 的數據，並且我們查看了帶有 VCM MAE 的 CGM 平台的數據，您會發現某些毒性往往與 C-max 相關。我們做出了在第二季度宣布的最初延遲的決定，而不是按順序進行，而是看看我們每三到四周的計劃可以達到多高，然後在那時，回過頭看看我們是否可以增加透過更頻繁地給藥來暴露，我們決定並行探索。

So, today, we don't know if dose-limiting toxicity is going to be C-max or AUC-related for this platform. One of the things we like to remind people, this is the first molecule on this platform that we've been able to get into this dose range. So, we are still learning how the platform behaves.

因此，今天，我們不知道該平台的劑量限制毒性是否與 C-max 或 AUC 相關。我們想提醒人們的一件事是，這是這個平台上我們能夠進入這個劑量範圍的第一個分子。因此，我們仍在了解該平台的行為。

As you recall, for our initial molecules, the 1592, the NaPi2b, the dose-limiting toxicity was driven by on-target toxicity. And that's where we saw the NaPi2b mediated ILD. In the so far, B7-H4, not just when we look at the competitors, has not really shown target mediated dose-limiting toxicity. So, this is an opportunity for us to really learn about our platform in these higher doses and exposures.

您還記得，對於我們最初的分子 1592 NaPi2b，劑量限制性毒性是由標靶毒性驅動的。這就是我們看到 NaPi2b 介導的 ILD 的地方。到目前為止，B7-H4 並沒有真正表現出標靶介導的劑量限制毒性，而不僅僅是我們觀察競爭對手。因此，這是我們在這些更高劑量和暴露下真正了解我們平台的機會。

Got it. And maybe just one more follow-up if I may. I think it's interesting that you talk about the C-max, your thoughts around C-max and how you're thinking about evaluating it to make sure that you have the optimal profile.

知道了。如果可以的話，也許我還會再做一次後續行動。我認為您談論 C-max、您對 C-max 的想法以及您如何考慮評估它以確保您擁有最佳配置文件很有趣。

Just going back to your comments and your press release, I think you emphasize a lot on your current efforts in understanding how to optimize the frequent dosing. So, as you think about your current progress to date, are you close in understanding how high you can go with 1660 or this platform? Thanks.

回到您的評論和新聞稿，我認為您非常強調您目前在了解如何優化頻繁給藥方面所做的努力。那麼，當您思考迄今為止的進展時，您是否已經接近了解 1660 或這個平台可以達到多高的水平？謝謝。

Yeah, I think, Brian, we've probably said as much as we can, and we are still in dose escalation, have not hit an MTD, and we'll just have to leave it at that for the time being.

是的，我想，Brian，我們可能已經說了盡可能多的內容，而且我們仍在劑量遞增中，尚未達到 MTD，我們只能暫時保留這一點。

Great. Thank you, Jason.

偉大的。謝謝你，傑森。

Sure.

當然。

(Operator Instructions) Asthika Goonewardene, Truist.

（操作員指示）Asthika Goonewardene，真理論者。

Hey, good morning, guys, and thanks for taking the question. So, I appreciate that you might be taking more than one dose level into the expansion cohort and that makes sense, but would you be conducting expansion cohorts with multiple frequencies running in parallel? So, maybe a Q2W, Q3W running in parallel at the same dose cohort, at the same dose level.

嘿，早上好，夥計們，感謝您提出問題。因此，我很高興您可能會在擴展隊列中服用不止一種劑量水平，這是有道理的，但是您會以並行運行的多個頻率進行擴展隊列嗎？因此，也許 Q2W、Q3W 在相同劑量組、相同劑量水平下並行運行。

And then, Marty, would you not be able to meet Project Optimus's requirements with the expansion cohorts? Let's say if you were to recruit maybe 30 to 40 patients in each cohort at a couple of different dose levels, would that not meet the FDA’s requirements, or do you think you need to do that pivotal phase study? And then I have a quick follow-up.

那麼，馬蒂，你的擴充部隊是否無法滿足擎天計畫的要求？假設您要在每個隊列中招募 30 至 40 名不同劑量水平的患者，這是否不符合 FDA 的要求，或者您認為您需要進行關鍵階段研究嗎？然後我會進行快速跟進。

With regards to your first question, yeah, when I say dose or recommended Phase 2 dose, I probably should be more explicit, it's recommended Phase 2 dose and schedule. And yes, it is possible that you would take two different dose schedules forward if that's the question is you really want to answer.

關於你的第一個問題，是的，當我說劑量或建議的第二階段劑量時，我可能應該更明確，這是建議的第二階段劑量和時間表。是的，如果您確實想回答這個問題，您可能會採取兩種不同的劑量計劃。

But at this point in time, it would be premature to speculate on how we're going to do that. Just the protocol is written. So, we have the flexibility that if we want to take a more frequent dose versus a less frequent dose forward, we could do that.

但目前推測我們將如何做到這一點還為時過早。只是寫了協議。因此，我們可以靈活地選擇，如果我們想要增加劑量而不是減少劑量，我們可以這樣做。

With regards to your second question, we are now getting purely into speculation as we have not had -- we're not coming forward with a specified registration-enabling study. So, I want to be clear, what I'm giving you is a theoretical.

關於你的第二個問題，我們現在純粹進行猜測，因為我們沒有進行過——我們沒有提出具體的註冊支持研究。所以，我想澄清一下，我給你的是理論。

To your point, generally most people are having to do some form of randomization for dose in the current environment. I think if you look at all the precedents out there today in the ADC space, they're doing randomization somewhere.

就您的觀點而言，通常大多數人都必須在當前環境下對劑量進行某種形式的隨機化。我認為，如果你看看當今 ADC 領域的所有先例，你會發現他們正在某個地方進行隨機化。

I don't think there's a strong rule on whether you do that as part of expansion or whether you do that as part of your pivotal. Ultimately, you're going to need some data justifying the therapeutic index, the benefit risk of your dose versus an alternative dose.

我認為對於是否將其作為擴展的一部分或是否將其作為關鍵的一部分來執行，沒有嚴格的規則。最終，您將需要一些數據來證明治療指數、您的劑量與替代劑量相比的益處風險。

And I think what that becomes a matter of -- to be frank, of efficiency of execution, et cetera. And those are all details that when we start talking about our expansion to registration plans, which we're not doing at this time, will go into our thinking there.

我認為這會成為一個問題——坦白說，是執行效率等等。這些都是當我們開始談論擴大註冊計劃時（我們目前沒有這樣做）的細節，我們將在那裡進行思考。

Got it. And then if you're in the enviable situation where you have pushed the dose and de-escalation and you're not seeing a big signal that you're approaching got dose-limiting, that's going to be dose-limiting, would you continue the escalation while also running the expansion at a couple of cohorts.

知道了。然後，如果您處於令人羨慕的情況，您已經增加了劑量並降級，但沒有看到您正在接近劑量限制的重大信號，這將是劑量限制，您會繼續嗎升級的同時還在幾個隊列中進行擴展。

I mean, it is possible if we get into that scenario. We do not -- as we said, we don't have to get to an MTD to declare a recommended Phase 2 dose to move forward. And that can be part of our judgment as the data emerges. If we're comfortable that we've got enough confidence in the dose and we want to continue to escalate and initiate expansion parallel, that isn't option for us. We have not made that decision today, and that will be based on data.

我的意思是，如果我們進入這種情況，這是可能的。正如我們所說，我們不需要達到 MTD 來宣佈建議的 2 期劑量才能繼續前進。隨著數據的出現，這可以成為我們判斷的一部分。如果我們確信我們對劑量有足夠的信心，並且我們希望繼續升級並同時啟動擴張，那麼這對我們來說不是選擇。我們今天還沒有做出這個決定，這將基於數據。

Great. Thanks, guys.

偉大的。謝謝，夥計們。

Thank you

謝謝

Justin Zelin, BTIG

賈斯汀·澤林，BTIG

Good morning and thanks for taking the question. With a discussion of unmet need for Topo summaries experience in resistant patients, can you talk to your confidence of differential activity of 16 of these patients?

早上好，感謝您提出問題。透過討論 Topo 未滿足的需求，總結抗藥性患者的經驗，您能否談談您對其中 16 名患者的差異活性的信心？

Yeah, maybe I can take that. I think there are a number of hypotheses that would maybe lend themselves to think that our payload might not be subject to the same resistance mechanism. So, as you're probably well aware, there have been a number of real-world data sets retrospective analysis of single sites that have shown that Topo isomers ADCs used after other Topo isomers ADCs, have a substantial degradation in time to event endpoints. And this data really started to come out last ESMO and it's been reinforced at ASCO and SABCS and other places.

是的，也許我可以接受。我認為有許多假設可能會讓我們認為我們的有效載荷可能不會受到相同的阻力機制的影響。因此，正如您可能很清楚的那樣，對單個站點的許多真實數據集回顧性分析表明，在其他拓撲異構體ADC 之後使用的拓撲異構體ADC 在到​​達事件終點的時間上有顯著的退化。這些數據在去年 ESMO 上才真正開始公佈，並在 ASCO 和 SABCS 等地方得到了加強。

There are papers out there that really speak to the mechanisms for how that resistance might occur. It might be related to the switch of Topo-1 enzyme complexes to Topo-2, which don't share sort of a chemical similarity, or could also be upregulation of PGP pumps. That's a pretty common resistance mechanism in cancer, just reducing drug concentrations in the cancer cells themselves.

有一些論文真正闡述了這種阻力如何發生的機制。這可能與 Topo-1 酶複合物向 Topo-2 的轉換有關，兩者沒有化學相似性，也可能與 PGP 泵的上調有關。這是癌症中非常常見的抗藥性機制，只是降低癌細胞本身的藥物濃度。

Our payload, a novel or a statin with a controlled bystander effect, is not subject to either of those mechanisms. It's not acting on Topo isomers. It's not acting on DNA. It's acting on the microtubules. And once metabolized, that payload is not a PGP pump substrate. So, those are at least theoretically reasons we would think that you might see some differential activity.

我們的有效載荷，一種新型藥物或具有受控旁觀者效應的他汀類藥物，不受這兩種機制的影響。它不作用於拓樸異構體。它不作用於 DNA。它作用於微管。一旦代謝，此有效負載就不再是 PGP 幫浦底物。因此，這些至少是理論上的原因，我們認為您可能會看到一些不同的活動。

Great. Thanks for taking the question.

偉大的。感謝您提出問題。

This concludes our question and answer session. I would like to turn the conference back over to CEO, Dr. Marty Huber, for any closing remarks.

我們的問答環節到此結束。我想將會議轉回給執行長 Marty Huber 博士發表閉幕詞。

Thank you, operator, and thanks, everyone, for dialing in. We'll be seeing some of you at New York at the Wedbush Healthcare conference and hope the rest of you enjoy the rest of your summer. This concludes the call operator. Thank you.

謝謝接線員，也謝謝大家撥電話。我們將在紐約韋德布希醫療保健會議上見到你們中的一些人，並希望你們其餘的人度過愉快的夏天。呼叫操作員到此結束。謝謝。

The conference has now concluded. Thank you for attending today's presentation. You may now disconnect.

會議現已結束。感謝您參加今天的演講。您現在可以斷開連線。