Mersana Therapeutics Inc (MRSN) 2023 Q4 法說會逐字稿

Good morning, and welcome to the Mersana Therapeutics fourth-quarter 2023 conference call and webcast. (Operator Instructions) Please note this call is being recorded.

早安，歡迎來到 Mersana Therapeutics 2023 年第四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。

I would now like to turn the call over to Jason Fredette, Senior Vice President, Investor Relations and Corporate Communications.

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.

謝謝接線員，大家早安。

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 relating to our platforms, product candidates, business strategy, clinical trial execution and results, business development efforts, and cash runway. Each of these forward-looking statements is subject to risks and uncertainties that could cause actual results to differ materially from those projected in such statements.

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、臨床試驗執行和結果、業務開發工作和現金跑道相關的聲明。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。

These risks and uncertainties are discussed in our quarterly report on Form 10-Q filed with the Securities and Exchange Commission on November 7, 2023 and in subsequent SEC filings. 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.

這些風險和不確定性在我們於 2023 年 11 月 7 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。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. It's great to be speaking with you again. Let's start today's call off with a brief description of our high-level aim here at Mersana.

謝謝傑森，大家早安。很高興再次與您交談。讓我們先簡單介紹一下 Mersana 的高階目標。

Although ADCs have firmly established a position at the forefront of oncology, there are significant platform and payload limitations that we believe are preventing this therapeutic class from realizing its full potential. At Mersana, we're focused on bringing forward innovations to address these limitations to meaningfully improve the efficacy and safety of ADCs.

儘管 ADC 已牢牢確立了在腫瘤學前沿的地位，但我們認為存在重大的平台和有效負載限制，阻礙了此類治療藥物充分發揮其潛力。在 Mersana，我們致力於提出創新來解決這些限制，從而有意義地提高 ADC 的功效和安全性。

Our goals are, first, to minimize dose-limiting platform toxicities. We believe the achievement of this goal can allow us to maximize the monotherapy potential of cytotoxic ADCs and also allow them to be used effectively in combination with other standard-of-care treatments, something that simply isn't possible with many of today's ADCs. Second, we aim to avoid resistance mechanisms that appear to be hampering certain ADCs. And third, we're striving to extend the field well beyond cytotoxics and establish an entirely new class of ADC therapies that elicit a targeted innate immune response to combat cancer.

我們的目標首先是最大限度地減少劑量限制平台毒性。我們相信，這一目標的實現可以使我們最大限度地發揮細胞毒性 ADC 的單一治療潛力，並使其能夠與其他標準護理治療有效結合使用，而這是當今許多 ADC 根本不可能實現的。其次，我們的目標是避免似乎阻礙某些 ADC 的抗藥性機制。第三，我們正在努力將該領域擴展到細胞毒素之外，並建立一種全新的 ADC 療法，引發有針對性的先天免疫反應來對抗癌症。

With that as a backdrop, let's turn our attention to the progress we're making in accomplishing these objectives, and let's begin with our proprietary auristatin payload that's being used in our next-generation cytotoxic ADC platform, Dolasynthen. When we developed this payload, one of our core objectives was to avoid the dose-limiting neutropenia and peripheral neuropathy that is reported with ADCs based on the vcMMAE platform and other first-generation ADC platforms.

以此為背景，讓我們將注意力轉向我們在實現這些目標方面所取得的進展，讓我們從我們的專有 auristatin 有效負載開始，該有效負載正在我們的下一代細胞毒性 ADC 平台 Dolasynthen 中使用。當我們開發此有效負載時，我們的核心目標之一是避免基於 vcMMAE 平台和其他第一代 ADC 平台的 ADC 所報告的劑量限制性中性粒細胞減少症和周圍神經病變。

Our payload has controlled bystander effect, meaning that it initially is membrane permeable and capable of bystander killing. However, it has also been designed to be enzymatically converted to an active metabolite that is much less membrane permeable, resulting in its accumulation in the tumor and avoidance of off-target toxicity.

我們的有效載荷具有受控旁觀者效應，這意味著它最初是膜可滲透的並且能夠殺死旁觀者。然而，它也被設計為透過酶轉化為膜滲透性較差的活性代謝物，從而導致其在腫瘤中積累並避免脫靶毒性。

While we view our payload as a core differentiator and advantage, the same can be said for the platform we're using to deliver that payload, Dolasynthen. We have presented extensive preclinical data in the past, demonstrating important advantages for Dolasynthen ADCs against ADCs produced using our own first-generation platform, Dolaflexin, and other platforms like vcMMAE.

雖然我們將有效負載視為核心差異化因素和優勢，但對於我們用來交付該有效負載的平台 Dolasynthen 來說也是如此。我們過去已經提供了大量的臨床前數據，證明了 Dolasynthen ADC 相對於使用我們自己的第一代平台 Dolaflexin 和 vcMMAE 等其他平台生產的 ADC 的重要優勢。

2024 provides us with the opportunity to begin presenting the clinical data. Next week, in Barcelona, at the European Society of Gynaecological Oncology, otherwise known as ESGO, clinical data will be presented for two discontinued product candidates, UpRi and XMT-1592. Both of these candidates utilize the same NaPi2b antibody and the same proprietary payload with controlled bystander effect. However, UpRi was developed using Dolaflexin, and 1592 was developed with Dolasynthen.

2024 年為我們提供了開始展示臨床數據的機會。下週，在巴塞隆納，歐洲婦科腫瘤學會（也稱為 ESGO）將公佈兩種已停產候選產品 UpRi 和 XMT-1592 的臨床數據。這兩種候選藥物都使用相同的 NaPi2b 抗體和具有受控旁觀者效應的相同專有有效負載。然而，UpRi 是使用 Dolaflexin 開發的，而 1592 是使用 Dolasynthen 開發的。

We believe these clinical data help to affirm that the severe neutropenia, peripheral neuropathy, and ocular toxicity that is frequently observed in trials of ADCs based on other platforms and payloads are uncommon with our payload. We also believe they clearly show that Dolasynthen further reduces platform toxicities compared with Dolaflexin.

我們相信這些臨床數據有助於證實，在基於其他平台和有效負載的 ADC 試驗中經常觀察到的嚴重中性粒細胞減少症、週邊神經病變和眼毒性在我們的有效負載中並不常見。我們也相信，它們清楚地表明，與 Dolaflexin 相比，Dolasynthen 進一步降低了平台毒性。

Following these presentations in mid-2024, we plan to share our initial clinical data for XMT-1660, our B7-H4-targeting Dolasynthen ADC. We continue to be pleased with the progress we're making in our Phase 1 trial of validating the safety and tolerability of XMT-1660 as a single agent in patients with solid tumors, including triple-negative and estrogen receptor-positive breast cancer, as well as ovarian and endometrial cancers.

在 2024 年中期進行這些演示之後，我們計劃分享 XMT-1660（我們的 B7-H4 靶向 Dolasynthen ADC）的初步臨床數據。我們對驗證 XMT-1660 作為單藥治療實體瘤患者（包括三陰性和雌激素受體陽性乳癌）的安全性和耐受性的 1 期試驗所取得的進展感到滿意。以及卵巢癌和子宮內膜癌。

The dose escalation portion of the trial is ongoing. In fact, we just recently escalated to a dose of 59 milligrams per meter squared, which is the highest dose that we have investigated clinically with the Dolasynthen ADC. A maximum tolerated dose for XMT-1660 still has not been established. In addition to continuing escalating dose, we are also continuing to enroll patients in backfill cohorts to optimize dose and schedule.

試驗的劑量遞增部分正在進行中。事實上，我們最近剛將劑量升級至每平方公尺 59 毫克，這是我們使用 Dolasynthen ADC 進行臨床研究的最高劑量。XMT-1660 的最大耐受劑量尚未確定。除了繼續增加劑量外，我們還繼續將患者納入回填隊列中，以優化劑量和時間表。

As is typical for Phase 1, we're enrolling a heavily pre-treated patient population. Today, single-agent chemotherapy is the standard of care for these types of patients, and their prognosis is exceedingly poor. For instance, the objective response rate in late-stage triple-negative breast cancer is estimated to be approximately 5% or less, with a duration of response that is less than four months.

正如第一階段的典型情況一樣，我們正在招募經過大量預先治療的患者群體。如今，單藥化療是此類患者的標準治療方法，但他們的預後極差。例如，晚期三陰性乳癌的客觀緩解率估計約為 5% 或更低，緩解持續時間不到四個月。

Today, most breast cancer patients here in the US are receiving in HER2 and Trodelvy early in their treatment. An increasing amount of data is emerging that shows patients are developing resistance following their first topo-1 ADC treatment. These factors are presenting an urgent unmet need for new ADCs with alternative payloads that do not share these resistance mechanisms. We are enrolling many patients who have previously received at least one of these topo ADCs in our Phase 1 clinical trial. And we're looking forward to sharing initial data mid-year, so we can begin to clinically characterize XMT-1660's efficacy and safety profile.

如今，美國大多數乳癌患者在治療早期都接受 HER2 和 Trodelvy 治療。越來越多的數據顯示，患者在首次使用 topo-1 ADC 治療後正在產生抗藥性。這些因素對具有不共享這些阻力機制的替代有效載荷的新型 ADC 提出了迫切的未滿足需求。我們正在招募許多之前至少接受過其中一種拓撲 ADC 的患者參加我們的 1 期臨床試驗。我們期待在年中分享初始數據，以便我們可以開始臨床表徵 XMT-1660 的功效和安全性。

Now, while we're very excited about XMT-1660 and Dolasynthen, we believe IO may be the next significant frontier for ADCs. Our Immunosynthen platform is designed to harness the power of STING and overcome the historic limitations of free systemic STING agonists and intratumoral injections. This platform has the potential to deliver a targeted and impactful one-two punch by activating STING in a target-dependent manner in tumor cells and in tumor-resident myeloid and dendritic cells, while also minimizing the risk of systemic exposure.

現在，雖然我們對 XMT-1660 和 Dolasynthen 感到非常興奮，但我們相信 IO 可能是 ADC 的下一個重要前沿領域。我們的Immunosynthen 平台旨在利用STING 的力量，克服免費全身STING 激動劑和腫瘤內注射的歷史限制。該平台有潛力透過在腫瘤細胞以及腫瘤駐留髓樣細胞和樹突狀細胞中以標靶依賴性方式激活STING 來提供有針對性的、有影響力的一二擊，同時還可以最大限度地降低全身暴露的風險。

XMT-2056 is our lead Immunosynthen ADC. We're currently in the process of restarting our Phase 1 trial of this HER2-targeting ADC following a lift of the clinical hold on this trial by the FDA in the fourth quarter of 2023. In Phase 1, we plan to enroll patients with a range of different HER2-positive tumors, including breast, gastric, colorectal, and non-small cell lung cancer, and we're looking forward to advancing dose escalation in 2024.

XMT-2056 是我們領先的免疫合成 ADC。在 FDA 於 2023 年第四季取消對該試驗的臨床擱置後，我們目前正在重新啟動這款 HER2 標靶 ADC 的 1 期試驗。在第一階段，我們計劃招募一系列不同 HER2 陽性腫瘤的患者，包括乳癌、胃癌、大腸癌和非小細胞肺癌，我們期待在 2024 年推進劑量遞增。

In addition to our independent programs, over the past two years, we also have entered into collaboration agreements with Johnson & Johnson, Merck KGaA, and GSK. We remain very much engaged with these companies as we seek to maximize the potential of our ADC platforms and product candidates.

除了我們的獨立專案外，在過去的兩年裡，我們還與強生公司、默克公司和葛蘭素史克公司簽訂了合作協議。我們仍然與這些公司保持密切合作，尋求最大限度地發揮我們的 ADC 平台和候選產品的潛力。

So in summary, Mersana entered 2024 with energy and excitement. We have two differentiated ADC platforms, platforms that we think could address significant limitations for today's ADCs. We also have two differentiated clinical-stage assets, an upcoming data readout on XMT-1660, and a strong balance sheet.

總而言之，Mersana 充滿活力和興奮地進入了 2024 年。我們有兩個差異化的 ADC 平台，我們認為這些平台可以解決當今 ADC 的重大限制。我們還擁有兩個差異化的臨床階段資產、即將在 XMT-1660 上讀出的數據以及強大的資產負債表。

On this latter point, let me turn the call over to our Chief Operating and Financial Officer, Brian DeSchuytner, to share more detail.

關於後一點，讓我將電話轉給我們的營運和財務長 Brian DeSchuytner，以分享更多細節。

Thank you, Marty. Let's begin with the financial highlights for the fourth quarter of 2023.

謝謝你，馬蒂。讓我們先了解 2023 年第四季的財務亮點。

We ended the year with approximately $209 million in cash, cash equivalents, and marketable securities. Net cash used in operating activities was approximately $32 million for the fourth quarter of 2023, which is down significantly from prior quarters, thanks to our restructuring and UpRi wind down efforts.

年底，我們擁有約 2.09 億美元的現金、現金等價物和有價證券。2023 年第四季經營活動使用的淨現金約為 3,200 萬美元，由於我們的重組和 UpRi 縮減工作，該數字較前幾季大幅下降。

From a cash expenditure standpoint, we expect to continue realizing benefits from these efforts in 2024. As a result, our capital resources are expected to be sufficient to support our current operating plan commitments into 2026. Please note that our cash runway guidance does not assume any potential milestone payments from our current collaborations or proceeds that we may realize from future collaborations.

從現金支出的角度來看，我們預計到 2024 年將繼續從這些努力中獲益。因此，我們的資本資源預計將足以支持我們目前到 2026 年的營運計畫承諾。請注意，我們的現金跑道指南並未假設我們目前合作中的任何潛在里程碑付款或我們可能從未來合作中實現的收益。

Turning to the income statement. Collaboration revenue for the fourth quarter of 2023 was $10.7 million, compared to $14.7 million for the same period in 2022. The year-over-year change was primarily related to the timing of research activities for the Johnson & Johnson collaboration and achievement of a Johnson & Johnson early development milestone in the fourth quarter of 2022.

轉向損益表。2023 年第四季的協作收入為 1,070 萬美元，而 2022 年同期為 1,470 萬美元。同比變化主要與強生公司合作的研究活動時間表以及強生公司在 2022 年第四季實現早期開發里程碑有關。

Research and development expenses for the fourth quarter of 2023 were $21.5 million, compared to $45.7 million for the same period in 2022. Approximately $2.2 million in non-cash stock-based compensation expenses and $3.7 million of external costs related to our UpRi wind down efforts were included in the R&D line in the most recent quarter. The year-over-year decline in R&D was primarily related to reduced manufacturing and clinical costs related to UpRi and XMT-2056 and reduced employee compensation costs, partially offset by increased clinical costs related to XMT-1660.

2023年第四季的研發費用為2,150萬美元，而2022年同期為4,570萬美元。最近一個季度的研發項目中包含約 220 萬美元的非現金股票補償費用和 370 萬美元的與 UpRi 逐步關閉工作相關的外部成本。研發年減主要與UpRi和XMT-2056相關的製造和臨床成本減少以及員工薪資成本減少有關，但部分被XMT-1660相關臨床成本增加所抵銷。

General and administrative expenses for the fourth quarter of 2023 were $10.1 million, compared to $14.8 million during the same period in 2022. Approximately $1.9 million in non-cash stock-based compensation expenses were included in G&A for the most recent quarter. The year-over-year decline in G&A expenses was primarily related to reduced consulting and professional fees and reduced employee compensation as a result of the restructuring plan we announced in July 2023.

2023 年第四季的一般及管理費用為 1,010 萬美元，而 2022 年同期為 1,480 萬美元。最近一個季度的一般管理費用中包含約 190 萬美元的非現金股票補償費用。一般管理費用較去年同期下降主要與我們於 2023 年 7 月宣布的重組計劃導致諮詢和專業費用減少以及員工薪酬減少有關。

Mersana's net loss for the fourth quarter of 2023 was $19.5 million, compared to a net loss of $44.9 million for the same period in 2022.

Mersana 2023年第四季的淨虧損為1,950萬美元，而2022年同期的淨虧損為4,490萬美元。

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

我們的業務更新到此結束。接線生，請開始接受觀眾提問嗎？

(Operator Instructions) Tara Bancroft, TD Cowen.

（操作員說明）Tara Bancroft，TD Cowen。

Hi, good morning. So maybe you could go into specific expectations for the mid-year 1660 update. And specifically, given the 1592 data that are coming next month, what takeaways can we use from that to take forward and increase our confidence in the 1660 data based on the new platform technology? Thanks.

早安.所以也許你可以對 1660 年中的更新提出具體的期望。具體來說，考慮到下個月即將發布的 1592 數據，我們可以從中得到哪些啟示來推進並增強我們對基於新平台技術的 1660 數據的信心？謝謝。

Thanks, Tara. So this is Jason. I'll start that. The mid-year data will be efficacy and safety tolerability data. We haven't specified exactly what we'll show just yet, but mid-year is the guidance, as you noted.

謝謝，塔拉。這就是傑森。我就開始吧。年中數據將是功效和安全耐受性數據。我們還沒有具體說明我們將展示什麼，但正如您所指出的，年中是指導。

Maybe I'll turn it over to Marty for the second part of the question.

也許我會把問題的第二部分交給馬蒂。

And just so I make sure I answer your questions, I understand is what can we learn from the ESGO data set on 1592. I think as we had noted was it's the same NaPi2b antibody, the same payload. The only difference is the scaffold, the Dolaflexin versus the Dolasynthen. And what we will show is the safety data from 1592 demonstrates what we would expect to see with our platform-related effects.

為了確保我能回答你的問題，我明白我們可以從 1592 年的 ESGO 資料集中學到什麼。我認為正如我們所指出的，它是相同的 NaPi2b 抗體，相同的有效負載。唯一的區別是支架，Dolaflexin 與 Dolasynthen。我們將展示 1592 的安全數據，展示了我們期望看到的與平台相關的效果。

And what we observed, or will show in the [upcoming] data is that, one, we continue to show an absence of peripheral neuropathy, absence of neutropenia, absence of ocular toxicity. But in addition, we plan to show that the data with 1592, the Dolasynthen, also has lower risk of some of the other platform toxicities that were observed with UpRi. And those details will be apparent between the two presentations.

我們觀察到的或將在[即將發布的]數據中顯示的是，第一，我們繼續顯示不存在周圍神經病變、不存在中性粒細胞減少症、不存在眼毒性。但除此之外，我們計劃證明 1592（Dolasynthen）的數據也具有較低的其他一些平台毒性的風險，這些毒性是在 UpRi 中觀察到的。這些細節在兩次演示中將顯而易見。

Okay, thank you.

好的謝謝。

Jonathan Chang, Leerink Partners.

喬納森·張 (Jonathan Chang)，Leerink 合夥人。

Hi, guys. Good morning. Thanks for taking my questions. First question, can you just remind us the decision-making process behind what happened with the second-gen NaPi2b program? And then just following up on the previous question, what the lessons there could be for the ongoing B7-H4 program?

嗨，大家好。早安.感謝您回答我的問題。第一個問題，您能否介紹一下第二代NaPi2b專案背後的決策過程？繼續上一個問題，正在進行的 B7-H4 計畫可以得到哪些教訓？

And then the second question, can you provide any color on how enrollment has progressed on the B7-H4 study and where you are in dose optimization? Thank you.

然後是第二個問題，您能否提供有關 B7-H4 研究的入組進展情況以及您在劑量優化方面的進展情況的任何資訊？謝謝。

Thank you, Jonathan. That sounds like three questions, but we'll take them in turn.

謝謝你，喬納森。這聽起來像是三個問題，但我們將依次回答它們。

So with respect to 1592, the original premise for that program was in lung cancer. And over the course of our explorations in lung cancer, we came to realize that the prevalence of the biomarker is much lower in lung cancer than was reported by the literature and was reported in ovarian cancer as well. And so that very much, given our cost of capital and the other opportunities available to us in our portfolio, drove the decisions around strategic reprioritization for 1592.

因此，就 1592 年而言，該計劃的最初前提是肺癌。在我們對肺癌的探索過程中，我們逐漸意識到，生物標記在肺癌中的盛行率比文獻報告的要低得多，在卵巢癌中也是如此。因此，考慮到我們的資本成本和我們投資組合中可用的其他機會，很大程度上推動了圍繞 1592 年策略優先順序調整的決策。

I think I'll pass it to Marty with respect to the 1660 question.

我想我會將有關 1660 問題的問題轉交給 Marty。

And with regards to learnings for B7-H4, one of the important observations from both 1536 and 1592 is that there was pneumonitis that we believe is associated with the presence of NaPi2b on type 2 pneumocytes that are in the lung. One of the things we've learned as we look at B7-H4, there is not that same level of expression or any expression on the pneumocytes for B7-H4.

關於 B7-H4 的研究，1536 年和 1592 年的重要觀察結果之一是，我們認為肺炎與肺部 2 型肺細胞上存在 NaPi2b 有關。當我們觀察 B7-H4 時，我們了解到的一件事是，B7-H4 的肺細胞上沒有相同的表達量或任何表達量。

And one of the reasons we were pleased to see the data from ESMO, from Seagen, and from Hansoh at ESMO, the last data set, they showed no evidence of target-mediated toxicity. So I think an important learning for us is that for the pneumonitis that we observed with NaPi2b is most likely on target, and we look forward to our data set with 1660.

我們很高興看到 ESMO、Seagen 和 ESMO 的 Hansoh（最後一個數據集）的數據，原因之一是它們沒有顯示靶點介導毒性的證據。所以我認為對我們來說一個重要的教訓是，我們用 NaPi2b 觀察到的肺炎最有可能達到目標，我們期待 1660 的資料集。

With regards to your enrollment question, I think we've essentially now escalated beyond dose level 6. We are now at 59 milligrams per meter squared. We are continuing to enroll in the backfills. As we've noted, it's up to 12 patients are in these backfills at dose levels. I think the other thing we've highlighted that we are looking at potential Q3, as well as alternative Q4 schedules. And so we remain -- we believe we're continuing to optimize dosing schedule for 1660.

關於您的註冊問題，我認為我們現在基本上已經升級到劑量等級 6 以上。我們現在的濃度為每平方公尺 59 毫克。我們正在繼續報名補缺。正如我們所指出的，在這些劑量等級的回填中最多有 12 名患者。我認為我們強調的另一件事是我們正在考慮潛在的第三季以及替代的第四季時間表。所以我們仍然相信我們會繼續優化 1660 的給藥方案。

Got it. Thank you.

知道了。謝謝。

Ashiq Mubarack, Citi.

阿希克·穆巴拉克，花旗銀行。

Hi, guys. Thanks for taking my questions, and congrats on the progress. I guess a couple for me. You said you're starting expansion cohorts for XMT-1660 in the second quarter. I guess when those cohorts get up and running, will you share which specific tumor types are being moved into the expansion phase? And also at that point, will you share what the go-forward dose will be? Or will we need to wait for those details at the mid-year data update? Thanks.

嗨，大家好。感謝您提出問題，並祝賀我的進展。我想對我來說有幾個。您說您將在第二季開始 XMT-1660 的擴展隊列。我想當這些隊列啟動並運行時，您會分享哪些特定的腫瘤類型正在進入擴展階段嗎？屆時，能否分享一下後續劑量是多少？或者我們需要等待年中資料更新時提供這些詳細資訊？謝謝。

Good questions. We haven't predefined that, I would say, so stay tuned on that front. We're operating in a competitive environment in the B7-H4 space, so TBD on that.

好問題。我想說，我們還沒有預先定義這一點，所以請繼續關注這方面。我們在 B7-H4 領域的競爭環境中運營，因此待定。

Okay, understood. And then maybe one more on 2056. It sounds like you're getting that study up and running again, but I'm just wondering what the gating factor is to getting dosing going? Or am I misunderstanding and that's already happened?

好的，明白了。2056 年也許還會有一場。聽起來你正在重新啟動並運行這項研究，但我只是想知道劑量的控制因素是什麼？或者我誤會了，那已經發生了？

We're taking the steps required to get the trial back underway as soon as possible. This includes re-engaging with our trial sites. So it's the internal process around IRB. But also when we changed the dose and made some other adjustments, that was a protocol amendment and then that has knock-on effects on databases and CROs, et cetera. So we're -- it's kind of the normal logistical stuff associated with a study restart. Those are underway.

我們正在採取必要的措施，盡快讓試驗重新開始。這包括重新參與我們的試用網站。這是圍繞 IRB 的內部流程。但當我們改變劑量並進行其他一些調整時，這就是一項方案修訂，然後對資料庫和 CRO 等產生了連鎖反應。所以我們——這是與研究重啟相關的正常後勤工作。這些正在進行中。

That's very helpful. Thanks very much.

這非常有幫助。非常感謝。

(Operator Instructions) Colleen Kusy, Baird.

（操作員說明）Colleen Kusy，Baird。

Hi, good morning. Thanks for taking our questions. Can you remind us how you're dealing with the B7-H4 biomarker in this Phase 1/2 dose escalation? Are you measuring it at baseline but not pre-selecting patients? And then would we expect any of the biomarker data in the mid-year update?

早安.感謝您回答我們的問題。您能否提醒我們，在 1/2 階段劑量遞增中，您是如何處理 B7-H4 生物標記的？您是否在基線時進行測量，但沒有預先選擇患者？那麼我們會期待年中更新中的任何生物標記數據嗎？

At this -- this is Marty. At this point in time, we are gathering data pre-treatment on B7-H4 expression. However, we are not using that to select for patients. Patients are enrolled regardless of the outcome of the test.

這是馬蒂。此時，我們正在收集 B7-H4 表達的預處理資料。然而，我們不會用它來選擇患者。無論測試結果如何，患者都會被納入。

With regards to data display, as Jason noted, we are in a highly competitive environment. Of note, neither Pfizer nor Hansoh shared their biomarker data, and so we will have to make a judgment call at the mid-year data presentation will we or will we not share that data.

關於數據顯示，正如 Jason 指出的那樣，我們處於一個競爭激烈的環境中。值得注意的是，輝瑞和豪森都沒有分享他們的生物標記數據，因此我們必須在年中數據發布會上做出判斷，我們是否會分享這些數據。

Great, that's helpful. Thank you. And then on 2056, how involved is GSK at this point in kind of restarting the study?

太好了，很有幫助。謝謝。然後到了 2056 年，葛蘭素史克在此時重啟這項研究的程度如何？

Well, maybe I'll take that. So the product has an option with GSK, as you will recall. And they have not exercised that option. And so we retain decision-making control over what we do in that product. But that said, GSK has been very engaged in the process. We're very pleased with the partnership.

好吧，也許我會接受。因此，您可能還記得，該產品可以選擇 GSK。他們還沒有行使這個選擇權。因此，我們保留對該產品所做的決策控制。但話雖如此，葛蘭素史克一直非常積極地參與這個過程。我們對這次合作非常滿意。

Great. Thanks for taking our questions.

偉大的。感謝您回答我們的問題。

Kaveri Pohlman, BTIG.

卡維裡·波爾曼，BTIG。

Hi. This is Christian. I'm on for Kaveri today. So actually, the previous question answered parts of what I was wondering. But for the Phase 1 trial for 1660, how much overlap do you expect to see between B7-H4 and some of the other ADC targets such as HER2, folate receptor alpha, and CDH6?

你好。這是基督教的。今天我要去卡維裡。事實上，上一個問題回答了我想知道的部分內容。但對於 1660 的 1 期試驗，您預期 B7-H4 和其他一些 ADC 標靶（例如 HER2、葉酸受體 α 和 CDH6）之間有多少重疊？

And my second question is for the STING ADC. Could you tell us how you're thinking about 2056 potentially fitting into the current treatment landscape? Is it mostly going to be a combination drug?

我的第二個問題是關於 STING ADC 的。您能否告訴我們您如何看待 2056 年可能融入當前的治療格局？它主要是一種組合藥物嗎？

Hi, it's Marty. With regards to 1660, while we don't have detailed data on that yet, one thing we do know is there's a trend for B7-H4 and PD-L1 on the tumor to not be overlapping. The Venn diagram of those two population tends to be fairly separate.

嗨，我是馬蒂。關於 1660，雖然我們還沒有詳細的數據，但我們確實知道的一件事是，腫瘤上的 B7-H4 和 PD-L1 有不重疊的趨勢。這兩個群體的維恩圖往往相當獨立。

With regards to folate receptor alpha, do not have any specific data available at this point in time. And I wouldn't want to speculate on that. But there is no -- we're not aware of any overlap in biology between the two targets, but as far as specific data that says whether the populations overlap or not, I can't give you that answer today.

關於葉酸受體α，目前沒有任何具體數據。我不想對此進行猜測。但我們不知道這兩個目標之間在生物學上有任何重疊，但就說明族群是否重疊的具體數據而言，我今天無法給你答案。

And with regards to the STING, we are certainly thinking in terms of combinations for 2056. We think one of the advantages of having a locally tumor-directed STING agonist is that that would allow you to do combinations with other systemic treatments. For example, you could give potentially an anti-PD-1 in a setting where you normally would not be able to because systemic STING activation, combined with the PD-1, would just be really too toxic for patients. So that is one of our long-term strategies is surely want to show activity monotherapy, but ultimately, we think it will be a combination agent.

至於 STING，我們當然正在考慮 2056 年的組合。我們認為局部腫瘤定向 STING 激動劑的優點之一是可以與其他全身性治療合併使用。例如，您可以在通常無法給予的環境中給予潛在的抗 PD-1，因為全身 STING 活化與 PD-1 結合，對患者來說毒性太大。因此，我們的長期策略之一肯定是希望展示活性單一療法，但最終，我們認為它將是一種聯合藥物。

And one last point on that, the actual epitope for HER2 is different than the HER2. So you could, in theory, actually do a HER2 combo.

最後一點，HER2 的實際抗原決定基與 HER2 不同。因此，從理論上講，您實際上可以進行 HER2 組合。

Okay, got it. Thank you. And if I can just throw one last one in there. Sorry if I missed this, but how many patients will be in the upcoming data for 1592 next week?

好，知道了。謝謝。如果我能把最後一顆丟進去就好了。抱歉，如果我錯過了這一點，但是下週即將發布的 1592 數據中將有多少患者？

For 1592, I think now, the ESGO abstract is available. And so in that data set, there were 31 patients.

我想現在 1592 年的 ESGO 摘要已經可用了。該資料集中有 31 名患者。

Okay, thank you.

好的謝謝。

(Operator Instructions) Michael Schmidt, Guggenheim.

（操作員說明）邁克爾·施密特，古根漢。

Hey, guys, good morning. Thanks for taking my questions. Just a couple more on 1660. In the Phase 1 study, could you comment on how the tumor histologies in the study compare perhaps to what Seagen, Pfizer have shown in their Phase 1? And I think they had a pretty decent signal in breast cancer. Is that -- is there overlap in sort of patient types in your study and theirs?

嘿，夥計們，早安。感謝您回答我的問題。1660 上還有幾個。在 1 期研究中，您能否評論一下該研究中的腫瘤組織學與 Seagen、輝瑞在 1 期研究中顯示的腫瘤組織學相比如何？我認為他們在乳癌方面有相當不錯的訊號。你的研究和他們的研究中的患者類型是否有重疊？

And then just as we think high level, you mentioned you're planning to initiate the expansion cohort soon. Any views on just general positioning longer term relative to the Seagen ADC in terms of differentiation, perhaps? Is it mainly lower tox on your end or increased efficacy or both perhaps? And then how do you think about differential development opportunities versus what they have been doing? Thanks so much.

然後，就在我們高層思考時，您提到您計劃很快啟動擴展隊列。也許對於相對於 Seagen ADC 的長期整體定位在差異化方面有什麼看法？主要是降低了您的毒性還是提高了功效，或者兩者兼而有之？那麼您如何看待差異化發展機會與他們一直在做的事情？非常感謝。

Good morning, Michael. I'm going to take the first part of your question, and then I'm going to turn it over to Brian to kind of talk to you about how we're thinking about the molecule longer term.

早上好，麥可。我將回答你問題的第一部分，然後我將把它交給布萊恩，讓他和你談談我們如何從長遠考慮這個分子。

With regards to the current data, we are enrolling patients with triple-negative breast cancer, hormone receptor-positive breast cancer, endometrial cancer, and ovarian cancer. So as part of the dose escalation, any one of those four histologies is eligible for the study.

就目前的數據而言，我們正在招募三陰性乳癌、荷爾蒙受體陽性乳癌、子宮內膜癌和卵巢癌患者。因此，作為劑量遞增的一部分，這四種組織學中的任何一種都適合這項研究。

Once we get into backfill, we can be a little more specific. And while we have not given detailed information on who we are enrolling, I think a couple of points can be made is, clearly, triple-negative breast cancer is an area of high unmet medical need, in which, after patients progress on Trodelvy and/or in HER2, there's essentially nothing for those patients. So you will -- I mean, while we're not giving the details of how many of each, that is a patient population that we will have in our data set.

一旦我們開始回填，我們就可以更具體一些。雖然我們沒有提供有關招募對象的詳細信息，但我認為可以提出幾點，很明顯，三陰性乳癌是一個醫療需求未得到高度滿足的領域，其中，在患者在 Trodelvy 和/或者在HER2 中，這些患者基本上沒有什麼。所以你會——我的意思是，雖然我們沒有給出每個患者有多少人的詳細信息，但這是我們數據集中的患者群體。

And if I can just expand on your question about differentiation and positioning, as Marty remarked earlier, one of the things that we're looking for in the ESMO data with any indication of a B7-H4 on-target types is you wouldn't see that, which is a nice validation of both the safety and the efficacy from those abstracts. As a reminder, we've compared Dolasynthen ACCs (sic - ADCs) versus vcMMAE ADCs extensively preclinically. And we show that our platform preclinically can deliver payload to the tumor much more efficiently and effectively.

如果我能詳細闡述您關於差異化和定位的問題，正如 Marty 之前所說，我們在 ESMO 數據中尋找的任何 B7-H4 目標類型跡象的一件事是，您不會看到這一點，這是對這些摘要的安全性和有效性的很好驗證。提醒一下，我們在臨床前廣泛比較了 Dolasynthen ACC（原文如此 - ADC）與 vcMMAE ADC。我們表明，我們的平台在臨床前可以更有效率、更有效地將有效負載傳遞到腫瘤。

In addition, we've shown in our past clinical presentations for other product candidates that our payload appears to avoid the severe neutropenia or peripheral neuropathy that tend to be dose limiting with MMAE. And so when you think about what that means, it's about expanding what an ADC can do in the clinic and, whether that's combinations or earlier lines, to create very strong regimens.

此外，我們在過去對其他候選產品的臨床演示中表明，我們的有效負載似乎可以避免嚴重的中性粒細胞減少症或周圍神經病變，而這些疾病往往會限制 MMAE 的劑量。因此，當您思考這意味著什麼時，您會發現，這意味著擴展 ADC 在臨床中的作用，無論是組合還是早期產品線，都可以創建非常強大的治療方案。

I think if you contrast with the Hansoh, GSK, and sort of the topos in general, keep in mind that our payload is very much more orthogonal to that class. And many patients in this setting are receiving prior topo ADCs. And so we believe this could be consideration in the future landscape, and you see echos of that in sort of commentary around the Hansoh data.

我認為，如果你與 Hansoh、GSK 和一般的拓撲進行對比，請記住我們的有效負載與該類別更加正交。在這種情況下，許多患者正在接受先前的拓撲 ADC。因此，我們相信這可能是未來格局中的考慮因素，並且您可以在圍繞豪森數據的評論中看到這一點的迴響。

And the Hansoh program also seems to have relatively profound myelosuppression that raises similar considerations about combinations and moves into earlier lines. So we think that the landscape that's been established by that ESMO data disclosure leaves opportunity.

豪森計劃似乎也具有相對較深的骨髓抑製作用，這引發了對組合和進入早期產品線的類似考慮。因此，我們認為 ESMO 數據揭露所建立的格局留下了機會。

Great. Thanks so much.

偉大的。非常感謝。

Asthika Goonewardene, Truist.

Asthika Goonewardene，真理主義者。

Hey, good morning, guys, and thanks for taking my question. You guys just very nicely laid out how some of the design features for 1660 could be making a difference. And we look at things like duration of response and duration of therapy as good measures to confirm if that's actually had their clinical difference. So maybe I'll ask you guys this. Given what we know about some of the B7-H4 ADCs, what kind of duration of response or duration of therapy would you be looking for in 1660 to say, aha, this actually makes a difference in the clinic but with the patients treated with 1660?

嘿，早上好，夥計們，感謝您提出我的問題。你們很好地闡述了 1660 的一些設計功能如何發揮作用。我們將反應持續時間和治療持續時間等視為確認其是否確實存在臨床差異的良好衡量標準。所以也許我會問你們這個。鑑於我們對一些 B7-H4 ADC 的了解，您在 1660 中會尋找什麼樣的反應持續時間或治療持續時間，哈哈，這實際上在臨床上有所不同，但對於接受 1660 治療的患者來說？

Hi, it's Marty. One, I would like to put a little caveat on looking at duration of response in Phase 1 data sets, even with pretty robust fulsome data sets, is always challenging just because the number of responders to get a precise point estimate is always relatively limited. So we want to be a little careful about getting too obsessed on that early on in the development program.

嗨，我是馬蒂。第一，我想對第一階段資料集中的回應持續時間提出一點警告，即使有相當強大的、豐富的資料集，也總是具有挑戰性，因為獲得精確點估計的回應者數量總是相對有限。因此，我們要小心一點，不要在開發計劃的早期過於痴迷於此。

However, we do agree it's a very important question. And if you think about it, the standard of care, chemotherapy, has a 5% objective response rate. And by the way, that's not even in a -- that's the control arm from the current ADCs. That's not post-Trodelvy or post in HER2. And importantly, the duration of response for that control arm was less than four months.

然而，我們確實同意這是一個非常重要的問題。如果你想一想，標準治療化療的客觀緩解率為 5%。順便說一句，這甚至不在目前 ADC 的控制臂中。這不是 Trodelvy 後或 HER2 後的情況。重要的是，此控制臂的反應持續時間不到四個月。

So I think a DOR -- usually, when we think about these things, you'd like to see a six -- five, six. One of the things that we were very excited about from UpRi is, while overall, the response rate was lower, one of the things you'll see in the data is that the duration of response for those patients who did respond to UpRi was over seven months. So we think there's an opportunity to increase DOR. I think it's just going to be challenging to clearly demonstrate that in the initial data set.

所以我認為 DOR——通常，當我們考慮這些事情時，你會希望看到 6——5、6。UpRi 讓我們感到非常興奮的一件事是，雖然總體而言，回應率較低，但您在數據中看到的一件事是，那些對 UpRi 有回應的患者的回應持續時間已經結束七個月。所以我們認為有機會增加 DOR。我認為在初始數據集中清楚地證明這一點將具有挑戰性。

Got it. That's very helpful. I'm also wondering, you talked about how resistance emerging from prior payload exposure is an issue that's emerging a lot more in the breast cancer patient population. Will the Phase 1 data set -- the dose escalation data set give us any sort of clues or be able to parse out when patients who are developing resistance to prior payloads and show us what the efficacy of 1660 looks like in that? Or is that just too much to try and piece out of that data set that's coming up?

知道了。這非常有幫助。我還想知道，您談到了先前有效負載暴露所產生的抗藥性如何成為乳癌患者群體中越來越多出現的問題。第一階段資料集－劑量遞增資料集能否為我們提供任何線索，或能夠解析出何時對先前的有效負載產生抗藥性，並向我們展示 1660 的功效如何？或者說，嘗試從即將出現的資料集中拼湊出的資料是否太多了？

Yeah. So this is Jason again. So again, I think it would be a little premature for us to pigeonhole ourselves into specific cuts of the data at this stage. We did note neither Hansoh nor Seagen showed any responses transparently, at least in post-topo treated patients. But again, we're not going to commit to that today.

是的。這又是傑森。再說一遍，我認為現階段我們將自己歸入特定的資料片段還為時過早。我們確實注意到 Hansoh 和 Seagen 都沒有明顯地顯示出任何反應，至少在拓撲治療後的患者中是如此。但同樣，我們今天不會做出承諾。

Got it. Thanks for taking my questions, guys.

知道了。謝謝你們回答我的問題，夥伴們。

Brian Cheng, JPMorgan.

布萊恩鄭，摩根大通。

Great. Thanks for taking our questions this morning. Maybe first one is, from a modeling perspective, how should we think about the expense trajectory given your plan to move forward into potentially larger studies across a number of indications? And I have a quick follow-up. Thank you.

偉大的。感謝您今天早上提出我們的問題。也許第一個是，從建模的角度來看，考慮到您計劃進行跨多種適應症的潛在更大規模的研究，我們應該如何考慮費用軌跡？我有一個快速的跟進。謝謝。

Sure. Well, our cash runway guidance is based on our current operating plan commitment. That does include the early clinical development of both 1660 and 2056. But if I sort of double-click on your question, as you know, we don't provide forward-looking financial guidance, but you'll note in our press release and our remarks in the K that we've reported a significant reduction in OpEx in Q4 and have, since then, substantially completed our UpRi wind down. So we think this meaningfully simplified cost structure is going to enable our available funds to support our operating plan commitments into 2026.

當然。嗯，我們的現金跑道指導是基於我們目前的營運計劃承諾。這確實包括 1660 和 2056 的早期臨床開發。但如果我雙擊你的問題，正如你所知，我們不提供前瞻性財務指導，但你會在我們的新聞稿和 K 中的評論中註意到，我們報告了大幅減少第四季度的營運支出，從那時起，我們基本上已經完成了UpRi 的縮減。因此，我們認為這種有意義的簡化成本結構將使我們的可用資金能夠支持我們到 2026 年的營運計劃承諾。

Great. And then second is on the dose escalation work that you're doing for 1660. How does the latest escalation to 59 mg per meter squared compare to your peers who are also targeting B7-H4? Maybe you can also provide some color on the expected therapeutic window that you expect to see compared to your peers. Thank you.

偉大的。其次是你正在為 1660 所做的劑量遞增工作。與同樣針對 B7-H4 的同業相比，最新升級至每平方公尺 59 毫克的劑量如何？也許您還可以提供一些關於與同齡人相比您期望看到的預期治療窗口的資訊。謝謝。

We want to be careful on directly comparising across the ADCs for there are several differences in these molecules. I mean, not only do they have different amounts of payload, we have DAR 6, but in addition, the potency of the payloads is different.

我們在直接比較 ADC 時要小心，因為這些分子有些差異。我的意思是，不僅它們的有效載荷數量不同，我們有 DAR 6，而且有效載荷的效力也不同。

And then one fundamental difference is because of our scaffold, our Dolasynthen platform, with the approved drug-like properties and an antibody like half-lives, we end up having -- allowing a less frequent dosing either Q3 or Q4. But what that's associated with, if you think about it, is it's a slower clearance of the molecule because it has an antibody like half-life. So it gets very complicated to try to do a direct detailed comparison until we get the full data disclosure, and then we can start having that conversation.

然後一個根本的區別是因為我們的支架，我們的 Dolasynthen 平台，具有批准的類似藥物的特性和類似抗體的半衰期，我們最終允許在 Q3 或 Q4 中減少給藥頻率。但如果你仔細想想，這與該分子的清除速度較慢有關，因為它具有類似抗體的半衰期。因此，在我們獲得完整的資料揭露之前，嘗試進行直接的詳細比較變得非常複雜，然後我們就可以開始進行對話。

Great. Thank you, Marty. Thanks.

偉大的。謝謝你，馬蒂。謝謝。

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

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

Thank you, operator, and thanks, everyone, for dialing in. We hope to see some of you in the next couple of weeks at ESGO, as well as Cowen and at Leerink. So that concludes the call, operator. Thank you.

謝謝接線員，也謝謝大家撥電話。我們希望在接下來的幾週內在 ESGO、Cowen 和 Leerink 見到你們中的一些人。接線生的通話就這樣結束了。謝謝。

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

謝謝。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。