Lite Strategy Inc (LITS) 2023 Q4 法說會逐字稿

Good day and welcome to the MEI fiscal year-end earnings call. My name is Gary and I will be the conference facilitator today. (Operator Instructions)

美好的一天，歡迎參加 MEI 財年終收益電話會議。我叫加里，我將擔任今天的會議主持人。 （操作員說明）

Please note today's event is being recorded.

請注意今天的活動正在錄製中。

I would now like to turn the conference over to David Walsey, Senior Vice President of Corporate Affairs at MEI Pharma. Please go ahead, sir.

我現在想將會議轉交給 MEI Pharma 公司事務資深副總裁 David Walsey。請繼續，先生。

Thank you, Gary. Hello and thank you for joining the MEI Pharma conference call today. My name is David Walsey and I'm Senior Vice President of Corporate Affairs for MEI. With me today on the call from MEI are David Urso, President and Chief Executive Officer; Jay File, Chief Financial Officer; and Dr. Richard Ghalie, Chief Medical Officer.

謝謝你，加里。您好，感謝您今天參加 MEI Pharma 電話會議。我叫 David Walsey，是 MEI 企業事務資深副總裁。今天與我一起參加 MEI 電話會議的是總裁兼執行長 David Urso；傑伊‧菲勒，財務長；和首席醫療官理查德·加利博士。

Before turning the call over to David for opening remarks, I'd like to remind you that during today's call, we'll be making forward-looking statements. Certain information contained in this communication that are not historical in nature are forward-looking statements within the meaning of the Safe Harbor provisions of the Private Securities Litigation Reform Act of 1995, including, without limitation, statements regarding the potential safety, efficacy, and regulatory and clinical progress of our product candidates, including the anticipated timing for the initiation of clinical trials and the release of clinical trial data and our expectations surrounding potential regulatory submissions, approvals, and timing thereof, our business strategy and plans, sufficiency of our cash, cash equivalents, and short-term investments to fund our operations.

在將電話轉交給大衛致開幕詞之前，我想提醒您，在今天的電話會議中，我們將做出前瞻性聲明。本新聞稿中包含的某些非歷史資訊屬於 1995 年《私人證券訴訟改革法案》安全港條款含義內的前瞻性陳述，包括但不限於有關潛在安全性、有效性和監管的陳述。我們的產品候選人的臨床進展，包括啟動臨床試驗和發布臨床試驗數據的預期時間，以及我們對潛在監管提交、批准及其時間的期望，我們的業務戰略和計劃，我們的現金充足性，現金等價物和短期投資為我們的營運提供資金。

You should be aware that our actual results could differ materially from those contained in the forward-looking statements, which are based on management's current expectations and are subject to a number of risks and uncertainties, including but not limited to: our failure to successfully commercialize our product candidates; the availability or appropriateness of utilizing the FDA's accelerated approval pathway for our product candidates; final data from our preclinical studies and completed clinical trials may differ materially from reported interim data from ongoing studies and trials, costs, and delays in the development and/or FDA approval, or the failure to obtain such approval for our product candidates; certainties or differences interpretation in the clinical trial results; uncertainty regarding the impact of rising inflation and the increase in interest rates as a result; potential economic downturn; activist investors; our inability to maintain or enter into and the risks resulting from our dependence upon collaboration or contractual arrangements necessary for the development, manufacture, commercialization, marketing, sales, and distribution of any products; competitive factors; our inability to protect our patents or proprietary rights and obtain necessary rights to third-party patents and intellectual property to operate our business; our inability to operate our business without infringing the patents and proprietary rights of others; general economic conditions; the failure of any products to gain market acceptance; our inability to obtain any additional required financing; technological changes; government regulation; changes in industry practice; and onetime events.

您應該意識到，我們的實際結果可能與前瞻性陳述中包含的結果有重大差異，前瞻性陳述基於管理層當前的預期，並受到許多風險和不確定性的影響，包括但不限於：我們未能成功商業化我們的候選產品；針對我們的候選產品使用 FDA 加速審批途徑的可用性或適當性；我們的臨床前研究和已完成的臨床試驗的最終數據可能與正在進行的研究和試驗、成本以及開發和/或FDA 批准的延遲或未能獲得我們的產品候選者的批准的中期報告數據存在重大差異；臨床試驗結果的確定性或差異解釋；通膨上升和由此導致的利率上升的影響存在不確定性；潛在的經濟衰退；激進投資者；我們無法維持或承擔因我們依賴開發、製造、商業化、行銷、銷售和分銷任何產品所需的合作或合約安排而產生的風險；競爭因素；我們無法保護我們的專利或專有權並獲得第三方專利和智慧財產權的必要權利來經營我們的業務；我們無法在不侵犯他人專利和專有權利的情況下經營我們的業務；一般經濟狀況；任何產品未能獲得市場認可；我們無法獲得任何額外所需的融資；技術變革；政府監管；行業慣例的變化；和一次性事件。

We do not intend to update any of these factors or to publicly announce the results of any revisions to these forward-looking statements. Under US law, a new drug cannot be marketed until it has been investigated in clinical studies and approved by the FDA as being safe and effective for the intended use.

我們無意更新任何這些因素或公開宣布這些前瞻性陳述的任何修訂結果。根據美國法律，新藥只有經過臨床研究並經 FDA 批准對預期用途安全有效後才能上市。

With that, I'll now turn the call over to David Urso.

現在，我將把電話轉給大衛·烏爾索。

Thank you, David, and thank you all for joining us today. On today's call, I'll make some opening remarks and then turn the call over to Richard Ghalie, our Chief Medical Officer, to review our progress. Jay File, our Chief Financial Officer, will then provide some brief financial comments before moving to Q&A.

謝謝大衛，也謝謝大家今天加入我們。在今天的電話會議上，我將做一些開場白，然後將電話轉給我們的首席醫療官理查德·加利（Richard Ghalie），以回顧我們的進展。然後，我們的財務長 Jay File 將提供一些簡短的財務評論，然後再進行問答。

Before getting started, I want to welcome Jay. He was just appointed our CFO as of August 1. So this is his first earnings call at MEI and we're very happy to have him on the team.

在開始之前，我想歡迎傑伊。他剛被任命為 8 月 1 日作為我們的財務長。這是他在 MEI 的第一次財報電話會議，我們很高興他加入團隊。

With that said, I'll make a brief statement regarding the termination of the merger agreement with Infinity Pharmaceuticals before moving on to review our business. Regarding that proposed transaction, while we believe the potential upside of the Infinity merger was compelling for MEI stockholders, we value the perspective of our stockholders. With the proposed transaction behind us, we're committed to pursuing our two promising clinical-stage programs as a standalone company.

話雖如此，在繼續審查我們的業務之前，我將就終止與 Infinity Pharmaceuticals 的合併協議發表簡短聲明。關於擬議的交易，雖然我們相信 Infinity 合併的潛在好處對 MEI 股東來說很有吸引力，但我們重視股東的觀點。隨著擬議的交易的完成，我們致力於作為一家獨立公司開展兩個有前景的臨床階段項目。

Looking ahead over the next few quarters, we see important opportunities in the continued progress of our two clinical-stage oncology programs, voruciclib and ME-344. I would like to use this call to provide an update on the status of these programs and why we're optimistic about their potential.

展望未來幾個季度，我們看到兩個臨床階段腫瘤計畫 voruciclib 和 ME-344 持續進展的重要機會。我想透過這次電話會議提供有關這些計劃的最新狀態以及我們對其潛力持樂觀態度的原因。

Both of our assets represent novel mechanisms of action. Voruciclib is an oral CDK9 inhibitor and ME-344 is a mitochondrial inhibitor that inhibits the OXPHOS pathway. We are investigating the potential of these compounds to overcome resistance mechanisms to standard-of-care therapies: the BCL2 inhibitor, venetoclax or voruciclib; and the VEGF inhibitor, bevacizumab, in the case of ME-344.

我們的兩種資產都代表了新穎的作用機制。 Voruciclib 是一種口服 CDK9 抑制劑，ME-344 是一種抑制 OXPHOS 途徑的粒線體抑制劑。我們正在研究這些化合物克服標準護理療法抗藥性機制的潛力：BCL2 抑制劑、venetoclax 或 voruciclib； ME-344 的情況是 VEGF 抑制劑貝伐珠單抗。

The ongoing advancement of each program is based on nonclinical, and in the case of ME-344, clinical data supporting proof of principle for the respective combinations. We chose these combination approaches based on clear hypotheses to address the known resistance mechanisms of each standard-of-care therapy, clear medical need, and significant commercial opportunities.

每個項目的持續進展都是基於非臨床，對於 ME-344，臨床數據支持各個組合的原理證明。我們基於明確的假設來選擇這些組合方法，以解決每種標準護理療法的已知抗藥性機制、明確的醫療需求和重大的商業機會。

We are working with some of the leading oncologists in the country in both of our clinical studies, and we're pleased with their level of engagement and interest in our programs. We expect data readouts from each program in the coming months.

我們正在與國內一些領先的腫瘤學家合作進行兩項臨床研究，我們對他們對我們計畫的參與程度和興趣感到滿意。我們預計在未來幾個月內會讀出每個程式的數據。

With respect to voruciclib, as previously reported, we've seen promising data from our ongoing Phase 1 study. Recall that voruciclib has a selective CDK9 inhibitor, regulates the transcription of MCL-1, and through that mechanism, also potential to address a known venetoclax resistance mechanism. The ongoing Phase 1 study is evaluating voruciclib as a single agent and in combination with venetoclax, which is standard of care in AML and used in other hematologic malignancies as well.

關於 voruciclib，正如先前報導的那樣，我們從正在進行的 1 期研究中看到了有希望的數據。回想一下，voruciclib 具有選擇性 CDK9 抑制劑，調節 MCL-1 的轉錄，並且透過該機制，還有可能解決已知的 venetoclax 抗藥性機制。正在進行的 1 期研究正在評估 voruciclib 作為單藥以及與 Venetoclax 聯合使用，Venetoclax 是 AML 的標準治療方法，也用於其他血液惡性腫瘤。

Richard will provide more detail shortly. But in brief, voruciclib alone and in combination with venetoclax has been generally well tolerated in the Phase 1 study to date with no significant myelosuppression in patients with B-cell malignancies or AML. The results further demonstrate encouraging early clinical activity in heavily pretreated patients that progressed on venetoclax who were administered voruciclib monotherapy and at the initial dose level in combination with venetoclax. The planned voruciclib data readout in early 2024 is expected to include data from the dose ascending cohorts in the Phase 1 study evaluating voruciclib plus venetoclax in patients with AML.

理查德將很快提供更多細節。但簡而言之，迄今為止的 1 期研究中，單獨使用 voruciclib 以及與 Venetoclax 聯合使用時，總體耐受性良好，B 細胞惡性腫瘤或 AML 患者沒有出現明顯的骨髓抑制。結果進一步表明，在接受 voruciclib 單藥治療以及初始劑量水平與 Venetoclax 聯合治療的、接受 Venetoclax 治療後病情進展的患者中，早期臨床活性令人鼓舞。計劃於 2024 年初讀出的 voruciclib 數據預計將包括來自評估 voruciclib 加 Venetoclax 治療 AML 患者的 1 期研究中劑量遞增隊列的數據。

Here are some of the leading KOLs we are working with. We're pleased with how the study is enrolling.

以下是我們正在合作的一些領先的 KOL。我們對這項研究的招募情況感到滿意。

As for pending ME-344, we're pursuing a novel approach to cancer therapy with the combination of ME-344 and OXPHOS inhibitor that inhibits the production of ATP and mitochondria, and bevacizumab, a VEGF inhibitor, which inhibits the production of ATP through glycolysis to deprive cancer cells of the energy needed to proliferate.

至於懸而未決的ME-344，我們正在尋求一種新的癌症治療方法，結合使用ME-344 和OXPHOS 抑制劑（抑制ATP 和粒線體的產生）以及貝伐單抗（一種VEGF 抑制劑），透過抑制ATP 的產生糖解剝奪癌細胞增殖所需的能量。

Bevacizumab is an established standard of care in multiple solid tumors, including colorectal cancer. Our ongoing Phase 1b study is evaluating metastatic colorectal cancer patients with ME-344 plus bevacizumab. This novel approach to treatment has also generated enthusiasm among our investigators in the ongoing study.

貝伐單抗是多種實體腫瘤（包括大腸直腸癌）的既定治療標準。我們正在進行的 1b 期研究正在評估使用 ME-344 加貝伐單抗的轉移性大腸直腸癌患者。這種新穎的治療方法也引起了我們正在進行的研究中的研究人員的熱情。

In earlier clinical studies, ME-344 was generally well tolerated at the dose we're currently investigating and there was evidence of clinical activity as a single agent. We had a first look at the potential for this combination in a 42-patient controlled window of opportunity clinical study in HER2 negative breast cancer patients waiting for mastectomy.

在早期的臨床研究中，ME-344 在我們目前正在研究的劑量下通常具有良好的耐受性，並且有證據表明作為單一藥物的臨床活性。我們在一項 42 名等待乳房切除術的 HER2 陰性乳癌患者的對照機會期臨床研究中首次觀察了這種組合的潛力。

Richard will discuss the decrease in the proliferation in biomarker, Ki-67, observed in that study. We expect that the ME-344 data readout planned in the first half of 2024 will include initial safety and efficacy data from the first 20-patient cohort in the Phase 1b study evaluating ME-344 in combination with bevacizumab in patients with metastatic colorectal cancer.

Richard 將討論在該研究中觀察到的生物標記 Ki-67 增殖的減少。我們預計計劃於2024 年上半年公佈的ME-344 數據將包括1b 期研究中首批20 名患者隊列的初步安全性和有效性數據，該研究評估ME-344 與貝伐單抗聯合治療轉移性大腸直腸癌患者。

We believe that the potential value of both programs is notable given that the addressable market opportunities for voruciclib in combination with venetoclax and ME-344 in combination with bevacizumab are significant. Venetoclax is currently used across AML, CLL, and double-hit DLBCL and generated approximately $2 billion in 2022 worldwide sales.

我們認為，鑑於 voruciclib 與 Venetoclax 組合以及 ME-344 與貝伐珠單抗組合的可尋址市場機會巨大，這兩個項目的潛在價值是顯著的。 Venetoclax 目前用於治療 AML、CLL 和雙重打擊 DLBCL，2022 年全球銷售額約為 20 億美元。

Venetoclax sales are continuing to grow and are expected to generate $3.4 billion by 2028. Avastin and bevacizumab biosimilars are used to treat a variety of cancers, including colorectal cancer and ovarian cancer. 2022 worldwide Avastin and bevacizumab biosimilar sales reached $2 billion in 2022 and are expected to grow to $3.3 billion by 2028.

Venetoclax 的銷售額將持續成長，預計到 2028 年將產生 34 億美元的收入。阿瓦斯汀和貝伐珠單抗生物相似藥用於治療多種癌症，包括大腸直腸癌和卵巢癌。 2022年全球阿瓦斯汀和貝伐珠單抗生物相似藥銷售額將在2022年達到20億美元，預計2028年將成長至33億美元。

In short, MEI's pipeline is promising and presents substantial opportunity for delivering novel therapeutics for patients and value creation for MEI stockholders. Voruciclib and ME-344 have the potential in combination with current standard-of-care therapies to overcome known resistance mechanisms and improve patient outcomes.

簡而言之，MEI 的管道前景廣闊，為為患者提供新型療法和為 MEI 股東創造價值提供了巨大的機會。 Voruciclib 和 ME-344 有可能與目前的標準護理療法相結合，克服已知的抗藥性機制並改善患者的治療結果。

Each program is supported by nonclinical, and in the case of ME-344, clinical data, demonstrating antitumor activity and mechanistic proof-of-concept for the combinations being evaluated. We anticipate reporting data for voruciclib early in calendar 2024 and in the first half of 2024 for ME-344. We look forward to these data readouts and the next steps these data will form.

每個項目都得到非臨床數據的支持，就 ME-344 而言，也得到臨床數據的支持，證明所評估的組合的抗腫瘤活性和機械概念驗證。我們預計 voruciclib 的數據將在 2024 年初報告，ME-344 的數據將在 2024 年上半年報告。我們期待這些數據的讀出以及這些數據將形成的下一步。

I will now turn the call over to Richard Ghalie, our Chief Medical Officer, to provide additional details on our pipeline. Following Richard's remarks, Jay File, our Chief Financial Officer, will provide a brief financial overview before moving to Q&A.

我現在將把電話轉給我們的首席醫療官理查德·加利 (Richard Ghalie)，以提供有關我們的管道的更多詳細資訊。在理查德發表演講後，我們的財務長 Jay File 將在進行問答之前提供簡短的財務概述。

Thank you, David. And I'll begin first by discussing voruciclib, a selective oral CDK9 inhibitor drug candidate. The mechanism of action of voruciclib is depicted in this cartoon. Voruciclib block the transcription of MCL-1 and meet at the Pol II level of DNA transcription. In addition, voruciclib block -- it includes the stabilization of the NIC protein, which has a downstream effect on that pathway. In a moment, I will give more detail to the meaning of these two targets.

謝謝你，大衛。我將首先討論 voruciclib，一種選擇性口服 CDK9 抑制劑候選藥物。這張漫畫描述了 voruciclib 的作用機制。 Voruciclib 阻斷 MCL-1 的轉錄並在 DNA 轉錄的 Pol II 層面上相遇。此外，voruciclib 阻斷—它包括 NIC 蛋白的穩定性，該蛋白對該通路具有下游影響。稍後我將更詳細地解釋這兩個目標的含義。

voruciclib had a favorable PK and PD profiles that allow its use orally because it's bioavailable. It is selective to CDK9 compared to other CDK as shown to the table -- on the table to the right where they have more binding affinity and longer residence time for CDK9 compared to the other CDK.

voruciclib 具有良好的 PK 和 PD 特性，允許口服使用，因為它具有生物利用度。與其他 CDK 相比，它對 CDK9 具有選擇性，如表所示 - 在右側表格中，與其他 CDK 相比，它們對 CDK9 具有更高的結合親和力和更長的停留時間。

In addition, voruciclib had more selectivity to CDKs compared to other candidates. Voruciclib is potent with an IC50 ranging from 0.2 to 1.7 micromolar in a variety of cell line tested. And interestingly, it concentrates in tumors over plasma which is relevant in patients with solid tumors or lymphoid malignancies with tumors.

此外，與其他候選藥物相比，voruciclib 對 CDK 具有更高的選擇性。 Voruciclib 在多種測試的細胞系中均有效，IC50 範圍為 0.2 至 1.7 微摩爾。有趣的是，它集中在腫瘤而不是血漿中，這與實體瘤或患有腫瘤的淋巴惡性腫瘤患者有關。

Now let's focus on the two targets of interest. The protein MCL-1, it is known that its increase is associated with poor prognosis in patients with acute myeloid leukemia or AML and in a variety of B-cell malignancies. In addition, upregulation of MCL-1 is an established mechanism of resistance to venetoclax. As venetoclax inhibit BCL2, it can lead to stabilization of MCL-1 leading to resistance to venetoclax over time.

現在讓我們專注於兩個感興趣的目標。 MCL-1 蛋白，已知其增加與急性髓性白血病或 AML 以及多種 B 細胞惡性腫瘤患者的不良預後相關。此外，MCL-1的上調是venetoclax抗藥性的既定機制。由於 Venetoclax 抑制 BCL2，它可以導致 MCL-1 穩定，從而隨著時間的推移對 Venetoclax 產生抗藥性。

Independently and separately, we also know that MYC is overexpressed in a variety of cancers and tend to be associated with poor prognosis. In addition, the MYC pathway include KRAS mutation, which would be relevant for the discussion about the potential role of voruciclib.

獨立且單獨地，我們也知道 MYC 在多種癌症中過度表達，並且往往與不良預後相關。此外，MYC 路徑包括 KRAS 突變，這與 voruciclib 潛在作用的討論有關。

Let's begin first on the aspect of inhibition of MCL-1. As mentioned, it is relevant for AML and B-cell malignancies and as a way to address venetoclax resistance. MEI focus its initial development in the hematologic malignancy beginning with AML. The reason we selected AML is because venetoclax-based therapies are standard of care and approved in elderly patients who are unfit to receive intensive chemotherapy. Based on the NCCH guidelines, it has been established also as the center of care in a variety of market research, including the one sided on the right.

我們先從MCL-1的抑制方面開始。如前所述，它與 AML 和 B 細胞惡性腫瘤相關，也是解決 Venetoclax 抗藥性的一種方法。 MEI 的初步開發重點是從 AML 開始的血液惡性腫瘤。我們選擇 AML 的原因是因為基於 Venetoclax 的療法是標準治療方法，並且批准用於不適合接受強化化療的老年患者。根據 NCCH 指南，它也被確立為各種市場研究（包括右側市場研究）的護理中心。

In addition, ongoing studies are being conducted to establish the role of venetoclax as part of the standard of care in chemotherapy eligible patients. Our hypothesis is voruciclib combined to venetoclax has the potential to restore sensitivity to venetoclax, and therefore, improved durability of response.

此外，正在進行的研究正在進行中，以確定維奈托克作為符合化療條件的患者護理標準的一部分的作用。我們的假設是 voruciclib 與 Venetoclax 組合有可能恢復對 Venetoclax 的敏感性，從而提高反應的持久性。

This slide summarizes the nonclinical data that support the combination of voruciclib and venetoclax in AML. This is in murine xenograft model. In panel A, it shows suppression of MCL-1 well level. In panel B, it shows that either agent all alone has activity in AML, but the combination is synergistic with further increase in apoptosis level. And that corresponds to an improve in survival in the model depicted here in AML. We have similar data with the combination with venetoclax in CLL and diffuse large cell lymphoma models.

本投影片總結了支持 voruciclib 和 venetoclax 聯合治療 AML 的非臨床數據。這是小鼠異種移植模型。在圖 A 中，它顯示了 MCL-1 孔水平的抑制。 B 組中，顯示單獨使用任一藥物均具有治療 AML 的活性，但合併用藥可協同促進細胞凋亡水準的進一步增加。這對應於此處描述的 AML 模型中生存率的提高。我們在 CLL 和瀰漫性大細胞淋巴瘤模型中與 Venetoclax 合併使用也有類似的數據。

Now moving to describe the Phase 1 study. This is a typical Phase 1 dose escalation expansion study in patients with relapsed-refractory AML and B-cell malignancy in the first stage, which is the monotherapy dose escalation and in patient with relapsed and refractory AML for the combination with venetoclax stage.

現在開始描述第一階段研究。這是一項典型的1期劑量遞增擴展研究，第一階段是在復發難治性AML和B細胞惡性腫瘤患者中進行單藥劑量遞增，而在復發難治性AML患者中則與venetoclax聯合治療。

As part for Phase 1 studies, its endpoints consists of safety, pharmacokinetic. We are also collecting samples for biologic correlate primarily to look at the BH3 profiling and MCL-1 expression as well as molecular mutation analysis. And we will also collect, of course, activity data.

作為一期研究的一部分，其終點包括安全性、藥物動力學。我們也收集生物相關樣本，主要是為了觀察 BH3 分析和 MCL-1 表現以及分子突變分析。當然，我們也會收集活動數據。

The monotherapy dose escalation component has been completed with 40 patients enrolled, and we are now currently enrolling in the combination with venetoclax group in patients with AML. As mentioned, this is a two-stage component. First, a dose escalation going from 50 milligram every other day upward. And as of now, we have completed enrolment at the 150-milligram dose level.

單藥治療劑量遞增部分已經完成，已入組 40 名患者，目前我們正在入組 AML 患者與 Venetoclax 聯合治療組。如前所述，這是一個兩階段組件。首先，劑量從每隔一天 50 毫克遞增。截至目前，我們已經完成了 150 毫克劑量等級的註冊。

Once (inaudible) dose that is confirmed to have well tolerated as well as evidence of activity, then we will proceed to expansion cohort. Currently, there is one contemplated and additional expansion cohort will be discussed with the FDA. In total, this study will enrol over 100 patients with hematologic malignancies, including approximately 70 patients and the combination with venetoclax.

一旦（聽不清楚）劑量被確認具有良好的耐受性以及活性證據，那麼我們將繼續擴大隊列。目前，我們將與 FDA 討論一個預期的擴展隊列和額外的擴展隊列。總的來說，這項研究將招募超過 100 名血液系統惡性腫瘤患者，其中包括約 70 名患者以及與 Venetoclax 的合併治療。

This is a brief summary of the data observed in the monotherapy dose escalation. Primary data were presented at the ASH 2021 and additional data and final data were presented at some subsequent scientific meeting. In total, 40 patients were enrolled, all heavily pretreated with a median of 3, prior therapy ranging from 1 to up to 8 therapies in one patient.

這是單一療法劑量遞增中觀察到的數據的簡要總結。原始數據在 ASH 2021 上公佈，附加數據和最終數據在隨後的一些科學會議上公佈。總共有 40 名患者入組，所有患者均接受過嚴格的預處理，其中一名患者接受過 3 次先前治療，範圍從 1 次到最多 8 次。

Two-dose schedule evaluated initially daily continuously in 16 patients. And we have, at that time, pivoted to evaluate voruciclib on a 14-days on, 14-days off therapy, and a 28-day cycle. And the reason for this pivot is because we have seen in the daily dosing two patients' pneumonitis that we felt were confounded by patient having developed differentiation syndrome, seen an AML patient receiving targeted therapy, as well as prior allogeneic transplant with graft versus host disease.

最初每天對 16 名患者連續評估兩劑量方案。當時，我們轉向以 14 天治療、14 天停藥和 28 天為一個週期來評估 voruciclib。這樣做的原因是因為我們在每日給藥中看到兩名患者出現肺炎，我們認為這與患有分化綜合徵的患者混淆，看到一名接受標靶治療的AML 患者，以及先前接受過同種異體移植並患有移植物抗宿主疾病的患者。

When we switch to the two weeks on, two-weeks off schedule, we're able to dose escalate up to 200 milligram without seeing DLTs. We stopped dose escalation not because of safety reasons, but because we wanted to start pivoting to the combination with venetoclax, our target combination regimen.

當我們切換到兩週按計劃、兩週停計劃時，我們可以將劑量增加到 200 毫克，而不會看到 DLT。我們停止劑量遞增不是因為安全原因，而是因為我們想開始轉向與我們的目標組合方案維奈托克的組合。

With the monotherapy, we have seen patient having evidence of anti-tumor activity, including one patient with AML who has a morphologic leukemia-free state achieved and 5 of 10 patients with AML at the 200-milligram dose who have stable disease.

透過單一療法，我們看到患者俱有抗腫瘤活性的證據，包括一名 AML 患者達到了形態學上的無白血病狀態，以及 10 名接受 200 毫克劑量的 AML 患者中有 5 名病情穩定。

Importantly, we have seen in our collective laboratory studies done with collaboration at academic centers a decrease in MCL-1 and MYC using a single cell RNA sequencing from three patients with CLL and two patients with AML.

重要的是，我們在與學術中心合作進行的集體實驗室研究中發現，透過對三名 CLL 患者和兩名 AML 患者進行單細胞 RNA 測序，MCL-1 和 MYC 有所減少。

So overall, voruciclib as a monotherapy at a dose of up to 200 milligram only 14-days on, 14-days off schedule was well tolerated, had no DLT. We did not see drug-related neutropenia. We did not see Grade 3 or higher drug-related toxicity and no patients were discontinued due to drug-related toxicities.

因此，總體而言，voruciclib 作為單一療法，劑量高達 200 毫克，僅按計劃給藥 14 天，停藥 14 天，耐受性良好，沒有 DLT。我們沒有看到與藥物相關的中性粒細胞減少症。我們沒有發現 3 級或更高等級的藥物相關毒性，也沒有患者因藥物相關毒性而停藥。

As mentioned, we are now enrolling in the venetoclax combination. Up to now, we have not seen DLTs. The PK analysis of the earlier dose levels do not show drug-drug interactions. And we are seeing evidence of clinical activity at the low dose evaluated today, manifested by reducing transfusions, improved counts, response observed in some patients, and over 85% of patients continuing beyond cycle one, the DLT windows. Keep in mind, this is observed in patients who have been heavily pretreated with a median of two prior therapy, including venetoclax.

如前所述，我們現在正在註冊 Venetoclax 組合。到目前為止，我們還沒有看到DLT。早期劑量水準的 PK 分析未顯示藥物間交互作用。我們看到今天評估的低劑量臨床活性的證據，表現為減少輸血、改善計數、在一些患者中觀察到的反應，以及超過 85% 的患者在第一週期（DLT 窗口）後繼續治療。請記住，這種情況發生在接受過中位數兩次既往治療（包括維奈托克）的大量預處理的患者中。

Now let's turn the focus to voruciclib effect on MYC. As mentioned, MYC is overexpressed in a variety of cancer and tend to be associated with poor prognosis. There is no current treatment approved for MYC-mutated tumors. CDK9 inhibition lead to reduced transcription of MYC and stabilization, thus, going to have a potential treatment effect.

現在讓我們把焦點轉向voruciclib對MYC的影響。如前所述，MYC 在多種癌症中過度表達，並且往往與不良預後相關。目前尚無核准用於 MYC 突變腫瘤的治療方法。 CDK9 抑制導致 MYC 轉錄減少和穩定，因此將產生潛在的治療效果。

We have clinical data from the initial studies conducted in patients with solid tumors about the prior sponsor. Two studies were conducted: one using a two-weeks on, one-week off schedule; and the other one using a daily continuously schedule.

我們擁有先前申辦者的實體腫瘤患者進行的初步研究的臨床數據。進行了兩項研究：一項研究採用兩週工作、休息一周的計劃；另一項研究採用兩週工作計劃，休息一周。另一個使用每天連續的時間表。

Relevant to the discussion today is in the daily continuous scheduled study, samples were obtained from 25 patients with a variety of solid tumors and tested on a 10-gene biomarker with sample obtained at baseline and with each subsequent course of therapy. We have seen a decrease in ischemic expression in 60% of the patient tested in that study.

與今天討論相關的是每日連續預定研究，從 25 名患有各種實體瘤的患者中獲取樣本，並使用在基線和每個後續療程中獲取的樣本對 10 基因生物標誌物進行測試。我們發現研究中 60% 的測試患者的缺血性表現有所減少。

And here are shown on the two illustrative example of two patients circled are the MYC gene that will be evaluated, showing a decrease in MYC over time with each course of therapy. At MEI, we have further expanded the evaluation of that effect on MYC and KRAS by evaluating a number of cell lines listed here, including colorectal cancer and other tumors that had variety of KRAS mutation, G12C, but also others. And shown to the panel to the right is a dose response relationship between voruciclib dose and suppression of tumor growth in three different cell lines with different KRAS mutation.

這裡顯示的兩個說明性例子中，兩個患者的圈出是將要評估的 MYC 基因，顯示隨著每個療程的時間，MYC 有所減少。在 MEI，我們透過評估此處列出的許多細胞系，包括結直腸癌和其他具有多種 KRAS 突變、G12C 等的腫瘤，進一步擴大了對 MYC 和 KRAS 的影響的評估。右圖顯示的是 voruciclib 劑量與具有不同 KRAS 突變的三種不同細胞系中腫瘤生長抑制之間的劑量反應關係。

And lastly and of interest is combination of voruciclib with the KRAS inhibitor, sotorasib. This experiment was conducted in a pancreatic tumor cell model. This is intralesion of infusion of one or a combination of drug. And the readout is shown to the panel to the right where we see two types of analysis. One is the standard pathology with an HA staining that shows the control arm, either agent alone. And to the bottom-right panel, the combination showing an evidence of cell death, pyknotic cells, and also in the fluorescent staining, an increased number of cells died.

最後令人感興趣的是 voruciclib 與 KRAS 抑制劑 sotorasib 的組合。該實驗是在胰臟腫瘤細胞模型中進行的。這是一種或多種藥物組合輸注到病灶內。讀數顯示在右側面板上，我們可以看到兩種類型的分析。一種是標準病理學，HA 染色顯示對照組，單獨使用任一藥物。右下圖顯示細胞死亡、固縮細胞的組合，並且在螢光染色中，死亡細胞數量增加。

So that is my summary for the voruciclib program. Now I'm turning to description of ME-344, a mitochondrial inhibitor drug candidate. This is a very interesting and novel mechanism of action where the inhibition of the mitochondria is a dual effect: one on OXPHOS, and two, on purine synthesis, reminding that purine synthesis is made at the surface of mitochondrial cells.

這是我對 voruciclib 程式的總結。現在我要介紹 ME-344，一種粒線體抑制劑候選藥物。這是一種非常有趣且新穎的作用機制，其中粒線體的抑制具有雙重作用：一是對 OXPHOS 的影響，二是對嘌呤合成的影響，這提醒人們嘌呤合成是在粒線體細胞的表面進行的。

The relevance of that mechanism is illustrated the panels to the right, which I will simplify by saying that mitochondria generate ATP, which are essential for producing energy for cells. And that is done through the OXPHOS pathway. Blocking the OXPHOS with ME-344 would lead to a decrease in ATP source of energy and eventually, by a cascade of event, to potentially cell death.

右側的面板說明了該機制的相關性，我將透過說粒線體產生 ATP 來簡化它，這對於為細胞產生能量至關重要。這是透過 OXPHOS 途徑完成的。用 ME-344 阻斷 OXPHOS 將導致 ATP 能量來源減少，並最終透過一系列事件導致潛在的細胞死亡。

Separately, purine biosynthesis is done, as I said, at the surface of mitochondria, which ME-344 can block to reenact essential to cell proliferation and blocking purine biosynthesis could lead to a decrease in cell growth and proliferation.

另外，正如我所說，嘌呤生物合成是在粒線體表面完成的，ME-344 可以阻斷粒線體表面的細胞增殖，阻斷嘌呤生物合成可能會導致細胞生長和增殖減少。

This is a simple panel of over 200 cell lines that were tested for ME-344 activity in vitro. And as one can see, ME-344 is potent at the nanomolecule level and nearly all cell lines tested, except a few. MEI conducted two Phase 1 studies: one at the single-agent dose escalation to determine the safety, efficacy, and PK, and that study led to the determination that recommended Phase 2 dose for further development is 10 milligram per kilogram.

這是一個由 200 多個細胞系組成的簡單組，並在體外測試了 ME-344 活性。正如我們所看到的，ME-344 在奈米分子層級上是有效的，幾乎所有細胞係都經過測試，除了少數細胞系。 MEI 進行了兩項 1 期研究：一項是單藥劑量遞增，以確定安全性、有效性和 PK，該研究確定進一步開發的 2 期建議劑量為每公斤 10 毫克。

The next study evaluating ME-344 with the chemotherapy, topotecan, in a couple of type of solid tumors. 48 patients enrolled this study, myelosuppression due to topotecan was observed. We had disease stabilization at 49% of the patients. However, MEI decided to pursue the development of ME-344 in a different direction on the basis of biology.

下一項研究評估了 ME-344 與化療拓撲替康一起治療幾種類型的實體腫瘤。 48 名患者參加了這項研究，觀察了拓撲替康引起的骨髓抑制。 49% 的患者病情穩定。然而，MEI決定在生物學的基礎上朝不同的方向進行ME-344的發展。

However, before I go to that, this is a table summarizing the safety profile of ME-344 as a single agent in the Phase 1 study, pointing to the fact that neuropathy was seen only at doses higher than 10 milligram per mg kilogram was the dose limiting toxicity. It was not reported at lower doses.

然而，在我開始之前，這是一張總結 ME-344 作為單一藥物在 1 期研究中的安全性概況的表格，指出只有在劑量高於每毫克千克 10 毫克時才會出現神經病變。劑量限制性毒性。低劑量時未見報道。

Now let me describe the new strategy that we would like to employ ME-344 in combination with the anti-angiogenic agents, primarily Avastin or bevacizumab. This stems for a simple observation that when Avastin is administered to patient, it blocks the glycolytic energy pathway, leading to effect on cell growth.

現在讓我來描述我們希望將 ME-344 與抗血管新生藥物（主要是阿瓦斯汀或貝伐單抗）聯合使用的新策略。這源自於一個簡單的觀察：當給患者服用阿瓦斯汀時，它會阻斷糖解能量途徑，進而影響細胞生長。

However, cells are (technical difficulty) versus the ATP I mentioned earlier. Therefore, it is plausible that combining ME-344 to block the mitochondria's energy and VEGF inhibitors like Avastin with now having possibly of synthetic lethality and therefore, improving anti-tumor control.

然而，細胞（技術難度）是與我之前提到的 ATP 相對的。因此，將 ME-344 與 VEGF 抑制劑（如阿瓦斯汀）結合起來阻斷粒線體能量是合理的，現在可能具有合成致死性，從而改善抗腫瘤控制。

This hypothesis was tested initially in animal models, of which I present two: one, a colorectal cancer model; and one, a breast cancer model using ME-344 in combination with oral VEGF inhibitor, nintedanib and regorafenib. And seen on this slide is a decrease in tumor growth with the combination compared to either agent alone and improve survival in colorectal model.

這個假設最初在動物模型中得到了檢驗，其中我提出了兩個：一是結直腸癌模型；二是動物模型。一是使用 ME-344 合併口服 VEGF 抑制劑尼達尼布和瑞格非尼的乳癌模型。從這張投影片中可以看出，與單獨使用任一藥物相比，合併用藥可以減少腫瘤生長，並提高大腸直腸模型的存活率。

This led to a study by collaborators at the NCI Spain in Madrid, a multicenter study, a proof-of-concept study evaluating ME-344 and bevacizumab in patients with breast cancer. The recent breast cancer was selected because that is a window of opportunity for this type of mechanistic study where patients between diagnosis and definitive surgery has a period of time where this study could be conducted.

由此，馬德里西班牙 NCI 的合作者進行了一項多中心研究，這是一項評估 ME-344 和貝伐珠單抗對乳癌患者的概念驗證研究。選擇最近的乳癌是因為這是此類機制研究的機會窗口，在診斷和確定手術之間的患者有一段時間可以進行這項研究。

It was a randomized control study in 41 patients. Group A receive bevacizumab with ME-344, just one cycle, and Group B received bevacizumab alone. The readout was a PET scan to look at tumor vascularization and tumor biopsy, looking primarily at the biomarker of tumor proliferation called Ki-67.

這是一項針對 41 名患者的隨機對照研究。 A 組接受貝伐單抗合併 ME-344，僅一個週期，B 組僅接受貝伐單抗。讀出的是 PET 掃描，用於觀察腫瘤血管化和腫瘤活檢，主要觀察稱為 Ki-67 的腫瘤增殖生物標記。

Results are illustrated on this slide. Group A, again, is the combination of ME-344 and bevacizumab in green. As you can see, looking at all patients enrolled on this study, there was a significant decrease of Ki-67 compared to an observed with bevacizumab alone.

結果如這張投影片所示。 A 組同樣是 ME-344 和綠色貝伐珠單抗的組合。如您所看到的，觀察參與本研究的所有患者，與單獨使用貝伐單抗觀察到的結果相比，Ki-67 顯著下降。

Focusing now on the subset of patients in this study who had a tumor normalization -- vascularization normalization by PET, this effect is further enhanced. This led us to the decision now to proceed in a clinical trial with clinical readout. And we selected colorectal cancer as the first study to evaluate the combination because it's an unmet need and Avastin is used in that setting.

現在關注本研究中透過 PET 實現腫瘤正常化（血管化正常化）的患者子集，這種效果進一步增強。這導致我們現在決定進行臨床試驗並進行臨床讀數。我們選擇大腸直腸癌作為第一個評估該組合的研究，因為這是一個未滿足的需求，而阿瓦斯丁就是在這種情況下使用的。

So this is a Phase 1/2 study in patient relapsed colorectal cancer after failure of all standard therapy. Primary objective is progression-free survival. Second objective are survival and safety. The study is conducted in separate cohort, beginning with cohort 1 and using the same dose and schedule that was used in the breast cancer study.

這是一項針對所有標準治療失敗後復發性大腸直腸癌患者的 1/2 期研究。主要目標是無惡化存活。第二個目標是生存和安全。該研究是在單獨的隊列中進行的，從隊列 1 開始，使用與乳癌研究相同的劑量和時間表。

20 patient will be enrolled and the readout will be four months after the last patient is enrolled. And considered as a positive outcome is a PFS at four months of 20% or higher. Then that will lead to evaluation of a second cohort and subsequent dual cohort to be discussed with the FDA.

將登記 20 名患者，讀數將在最後一名患者登記後四個月內進行。四個月的 PFS 達到​​ 20% 或更高被認為是正面的結果。然後，這將導致對第二個隊列的評估以及隨後與 FDA 討論的雙隊列的評估。

With that, I conclude the clinical update, and we'll turn it to Jay File to talk about the financial overview.

至此，我總結了臨床更新，我們將把它交給 Jay File 討論財務概況。

Thank you, Richard. As reported earlier today, as of June 30, 2023, MEI had $100.7 million in cash, cash equivalents, and short-term investments with no outstanding debt. We believe our cash balance is sufficient to fund operations for at least the next 12 months and through the reporting of clinical data readouts from the ongoing and planned voruciclib and ME-344 Phase 1 and Phase 1b clinical programs, respectively.

謝謝你，理查。正如今天稍早報道的，截至 2023 年 6 月 30 日，MEI 擁有 1.007 億美元的現金、現金等價物和短期投資，沒有未償債務。我們相信，我們的現金餘額足以為至少未來 12 個月的營運提供資金，並分別報告正在進行和計劃中的 voruciclib 和 ME-344 1 期和 1b 期臨床項目的臨床數據讀數。

I look forward to any questions on the broader set of financial information reported earlier today during the Q&A portion of the call. I'll turn that back to David.

我期待在今天早些時候電話問答部分就更廣泛的財務資訊提出任何問題。我會把這個問題轉回給大衛。

Thanks, Jay. As you've heard today, I believe we have two exciting programs with expected data readouts beginning with voruciclib early in calendar 2024 and in the first half of 2024 for ME-344. With the promising pipeline and capital to support our near-term development plans, we're excited about the potential to create stockholder value and deliver improved therapeutic options for patients.

謝謝，傑伊。正如您今天所聽到的，我相信我們有兩個令人興奮的計劃，預計將在 2024 年初使用 voruciclib 讀取數據，並在 2024 年上半年讀取 ME-344 的數據。憑藉有前途的管道和資本來支持我們的近期發展計劃，我們對創造股東價值和為患者提供改進的治療選擇的潛力感到興奮。

Before we turn to Q&A, I'd like to briefly acknowledge that two of our stockholders, Anson and Cable Car, have initiated a consent solicitation process and separately submitted three director candidates to stand for election at the company's Annual Stockholder Meeting this year. We have had several conversations with Anson and Cable Car as part of ongoing efforts to resolve the situation and remain open to further discussion. We will appropriately address the actions of these stockholders in due course.

在我們進行問答之前，我想簡單地確認一下，我們的兩個股東 Anson 和 Cable Car 已經啟動了徵求同意程序，並分別提交了三名董事候選人，以參加今年公司年度股東大會的選舉。作為解決這個問題的持續努力的一部分，我們與 Anson 和 Cable Car 進行了多次對話，並對進一步討論持開放態度。我們將適時妥善處理這些股東的行為。

For the purposes of this earnings call, we are here to discuss our programs and upcoming milestones. We ask that you please keep your questions to these topics.

為了本次財報電話會議的目的，我們在這裡討論我們的計劃和即將到來的里程碑。我們要求您將問題保留在這些主題上。

I'll now ask the operator to provide the instructions for asking questions and then open the call for Q&A.

我現在將要求接線員提供提問說明，然後打開問答通話。

(Operator Instructions)

（操作員說明）

Yale Jen, Laidlaw & Company.

耶魯‧詹 (Yale Jen)，萊德勞公司。

Good afternoon and thanks for taking the question as well as providing a clear view of what's happening currently. Maybe I start with a housekeeping question that you got about $100 million cash. And in the press release, you suggested that you have 12 months, maybe a little bit longer runway.

下午好，感謝您提出問題並清楚了解當前發生的情況。也許我會從一個內務問題開始，你大約有 1 億美元的現金。在新聞稿中，您建議有 12 個月，甚至更長一點的時間。

Given that you are still in Phase 1 -- 1/2 study, should we anticipate it to be a more conservative estimate or any additional thoughts behind that in terms of the runway? And I have some follow-up as well.

鑑於您仍處於 1-1/2 階段研究，我們是否應該預期它是一個更保守的估計，或者在跑道方面有任何其他想法？我也有一些後續行動。

Thanks, Yale. This is David. I would say it's conservative in the sense that we've got all the capital we need to do the Phase 1 programs as we're currently -- they're currently planned and as we have some ideas about augmenting them.

謝謝，耶魯。這是大衛。我想說這是保守的，因為我們已經擁有了進行第一階段項目所需的所有資本，因為我們目前正在計劃這些項目，我們有一些關於增強它們的想法。

But going into Phase 2 is really data driven. And so it's really impossible to speculate about the next phase of development for these programs. So I think it's an appropriate guidance in that respect. It's at least 12 months and covering the current work that we're doing. So you could characterize it as being, I guess, somewhat conservative, but we did say at least 12 months.

但進入第二階段其實是數據驅動的。因此，推測這些程序的下一階段的開發確實是不可能的。所以我認為這在這方面是一個適當的指導。至少 12 個月，涵蓋了我們目前正在做的工作。所以我想你可以將其描述為有點保守，但我們確實說過至少 12 個月。

Sure. And maybe just in terms of -- again, the housekeeping one, which is the top line. I understand the prior deals are completed. So should we anticipate some top line coming just because of the amortization? Or we should anticipate that to be stopped in the early and near term?

當然。也許只是就——再一次，家事服務而言，這是最重要的。據我所知，之前的交易已經完成。那麼，我們是否應該僅僅因為攤銷而預期一些收入？或者我們應該預期這種情況會在早期和短期內停止？

I'm sorry, could you repeat? We are having a little bit of trouble following the question. Could you please repeat it?

抱歉，您能再說一次嗎？我們在回答這個問題時遇到了一些麻煩。您能再說一次嗎？

Sure. In terms of the top-line revenue that you have this quarter, my question is that would that continue -- will it continue for the subsequent fiscal year or simply these revenue numbers just the amortization of the prior revenue received?

當然。就本季的營收而言，我的問題是這種情況會持續下去嗎？它會持續到下一個財年，還是只是這些收入數字只是之前收到的收入的攤銷？

Yeah. I mean, all the revenue we're recognizing is all KKC driven from our collaboration with them. So it's not anticipated to continue into the future.

是的。我的意思是，我們所確認的所有收入都是 KKC 透過與他們的合作獲得的。因此預計這種情況不會持續到未來。

Okay. Maybe the last question here is in the clinical side over voruciclib Phase 1 data readout. What should we anticipate specifically in terms of type of data? Would that -- other than the safety, would that be PK and would that be any biomarker or other aspect? Could you provide a little bit of color on that?

好的。也許這裡的最後一個問題是關於 voruciclib 一期資料讀出的臨床面向。在資料類型方面我們應該具體預期什麼？除了安全性之外，還有 PK 以及任何生物標記或其他方面嗎？你能提供一點顏色嗎？

Yes, this is Richard. Yes, it will be a combination of safety data primarily since this is the primary endpoint in Phase 1 study. Perhaps a recommended Phase 2 dose. There will be also PK data and biomarker analysis. All of them will be available.

是的，這是理查。是的，這將是安全資料的組合，主要是因為這是第一階段研究的主要終點。也許是建議的第二階段劑量。還將有 PK 數據和生物標記分析。所有這些都將可用。

What specific -- would you already have some biomarker in mind? If so, what that might be?

具體是什麼－您是否已經想到了一些生物標記？如果是這樣，那可能是什麼？

All right. So I've mentioned it when I present the monotherapy dose escalation, the biomarker that we are evaluating, our BCL1 profiling, particularly MCL-1 expression. We are looking at multiple molecular biomarkers such as MYC. And we will be looking at potentially other biomarkers that are relevant and directly to the effect of CDK9 on the target.

好的。因此，當我介紹單一療法劑量遞增、我們正在評估的生物標記、我們的 BCL1 分析（尤其是 MCL-1 表達）時，我已經提到了這一點。我們正在研究多種分子生物標記物，例如 MYC。我們還將研究與 CDK9 對標靶的影響相關且直接相關的其他潛在生物標記。

Okay. Okay. Great. Yeah, I'll get back to the queue. And thanks for the color.

好的。好的。偉大的。是的，我會回到隊列中。謝謝你的顏色。

I mean, I guess we could also say that just from a clinical perspective for the cohort 1 from ME-344, we will be looking at PFS. And for the voruciclib expansion cohort that's in our protocol right now, we'll be looking at how large. So those are just standard clinical endpoints for the two respective diseases.

我的意思是，我想我們也可以說，僅從 ME-344 第 1 組的臨床角度來看，我們將關注 PFS。對於目前我們協議中的 voruciclib 擴展隊列，我們將研究其規模有多大。所以這些只是這兩種疾病的標準臨床終點。

Actually, let me -- if I can maybe just follow up as well on that. You said a 20% or higher of the threshold. So moving forward for ME-344 study cohort 1. What other factors determine that? The 20% was the number for the cutoff?

事實上，讓我——如果我也可以跟進一下的話。你說的是20%或更高的門檻。那麼，繼續進行 ME-344 研究隊列 1。還有哪些因素決定這一點？ 20%是截止的數字嗎？

So that was a requirement or a gate that we reached in collaboration with the clinicians. We really need to dig into exactly what the patient population is before we really know what the meaning of that threshold is. It obviously depends on exactly the experience of each patient.

所以這是我們與臨床醫師合作達成的要求或門檻。在我們真正了解該閾值的含義之前，我們確實需要深入了解患者群體。顯然，這完全取決於每位患者的經驗。

And maybe again, one more question here, which is that: if compared to what your prior study in the breast cancer or non-small cell lung, was there any comparable number to that PFS?

也許這裡還有一個問題，那就是：如果與您先前對乳癌或非小細胞肺癌的研究相比，是否有任何可比較的 PFS 數字？

Yeah. This is Richard answering. So it's really two very different approach to therapy here. In the Phase 1 study in combination with chemotherapy, we were really looking at cytotoxic effect and looking at response as the primary endpoint.

是的。這是理查的回答。所以這其實是兩種截然不同的治療方法。在與化療結合的第一期研究中，我們真正關注的是細胞毒性效應，並將反應作為主要終點。

Here, we are really looking at a different approach, whether it's synthetic lethality by combining VEGF inhibitor with them mitochondria inhibitor, and therefore, the response rate is less relevant. More relevant would be the time to progression.

在這裡，我們實際上正在尋找一種不同的方法，無論是透過將 VEGF 抑制劑與粒線體抑制劑結合來實現合成致死性，因此，反應率的相關性較小。更相關的是進展時間。

Again, it's a very different disease. So it will be hard to compare breast cancer -- or rather I'm sorry, colorectal cancer on one hand with a prior study, which was done in ovarian cancer and small cell lung cancer.

再說一次，這是一種非常不同的疾病。因此，很難將乳癌——或者更確切地說，我很抱歉，大腸癌與先前針對卵巢癌和小細胞肺癌進行的研究進行比較。

Okay, great. That's very helpful. Thank you, all. I appreciate it.

好的，太好了。這非常有幫助。謝謝你們。我很感激。

Mr. Willey, your line is open on our end or perhaps, you haven't muted on yours.

威利先生，您的線路在我們這邊處於開放狀態，或者您的線路可能沒有靜音。

No, thanks for taking the questions. Maybe just one on voruciclib, one on 344, and then just a modeling or financial question. So on voruciclib, what's your expectations just around venetoclax retreatment, post-progression in the context of AML?

不，感謝您提出問題。也許只是 voruciclib 上的一個，344 上的一個，然後只是一個建模或財務問題。那麼，關於 voruciclib，您對 AML 病情進展後的 Venetoclax 再治療有何期望？

And I guess I ask the question because there's not a lot of data that's out there in the public domain on sort of re-treatment experience. In CLL, that's shown that you can resensitize patients to venetoclax -- with venetoclax alone. I'm just kind of curious, as you think about the data you're going to be generating, what's good, what's interesting? What is your working assumption around venetoclax retreatment response rates?

我想我問這個問題是因為公共領域沒有太多關於再治療經驗的數據。在 CLL 中，這表明您可以使患者對 Venetoclax 重新敏感——僅使用 Venetoclax。我只是有點好奇，當你思考你將要產生的數據時，什麼是好的，什麼是有趣的？您對維奈托克再治療反應率的工作假設是什麼？

Yeah. I mean, in the initial experience with venetoclax in the relapsed-refractory AML population was pretty limited. I think was like 19 patients and they saw about a 20% response rate. But as you know, that was in a venetoclax naïve population. Now everybody is getting venetoclax.

是的。我的意思是，在復發難治性 AML 族群中使用 Venetoclax 的初步經驗非常有限。我想大概有 19 位患者，他們的緩解率約為 20%。但如你所知，那是在未接觸過維奈托克的人群中。現在每個人都在服用venetoclax。

But I think when we talk to our advisors, it's still around the same threshold is what they would be excited by. I think it's a big deal if you can bring back response to a patient that progressed on venetoclax. And 20% to 30% response rate in that -- in this relapsed population, I think, would get everybody excited.

但我認為，當我們與顧問交談時，他們感到興奮的閾值仍然相同。我認為，如果你能讓服用維奈托克治療後病情出現進展的患者恢復反應，那就是一件大事了。我認為，在這個復發族群中，20% 到 30% 的回覆率會讓每個人都興奮不已。

Okay. And then 344, I think per clintrials.gov (sic - "clinicaltrials.gov"), it doesn't list any of the approved salvage regimens as allowable prior therapy. So are we to assume that these patients are going to be Lonsurf and regorafenib naïve?

好的。然後 344，我認為根據 clincials.gov（原文如此 - “clinicaltrials.gov”），它沒有列出任何已批准的挽救方案作為允許的先前治療。那麼我們是否可以假設這些患者從未接受過 Lonsurf 和瑞戈非尼治療？

This is Richard. So you're right; this is not listed on Clinical Trials, but the protocol is really abiding with what the FDA wanted. So patients should have received and progressed on or did not tolerate standard chemotherapy, which, as you know, platinum based, [energy based], 5-FU.

這是理查德.所以你是對的；這並未列入臨床試驗，但該方案確實符合 FDA 的要求。因此，患者應該接受標準化療並取得進展，或無法耐受標準化療，如您所知，標準化療是鉑類、[基於能量]、5-FU。

And in addition, if they have a mutation that is addressable, like BRAF, they have to receive it. If they are eligible for checkpoint inhibitors, they should have receive it or not tolerate it. And on this end, they could enrol in this study. So we may have patients who have received regorafenib and/or Lonsurf or not. So it's not a requirement. But we anticipate that some patient, and in fact, would have received them in this study.

此外，如果他們有可尋址的突變，例如 BRAF，他們就必須接受它。如果他們有資格接受檢查點抑制劑，他們應該接受或不耐受。為此，他們可以參加這項研究。因此，我們可能有接受過或未接受過瑞格非尼和/或 Lonsurf 治療的患者。所以這不是一個要求。但我們預計一些患者實際上會在這項研究中接受它們。

Okay. And then maybe just to follow up on the 20% four-month PFS rate that's required to gain the enrolment of stage 2. I guess when you look -- I think it was what the SUNLIGHT study that was just published, I think they saw a six-month PFS with Avastin and Lonsurf of north of 40%, and then I think with Lonsurf alone close to 20%.

好的。然後也許只是為了跟進獲得第二階段註冊所需的 20% 的四個月 PFS 率。我想當你看時——我認為這就是剛剛發表的 SUNLIGHT 研究，我認為他們看到了使用Avastin 和Lonsurf的6 個月PFS 約為40%，然後我認為單獨使用Lonsurf 接近20%。

So I'm just trying to, I guess, maybe think about the threshold that you're establishing here in the context of some of the historical data that's out there.

所以我想，我只是想考慮一下您在現有的一些歷史資料的背景下在這裡建立的閾值。

You're absolutely right about this. The reported -- the Phase 3 study, in fact, that was reported at ASCO GI came in when we were just launching this study. So just let me explain where the 20% threshold of came, but then also what it means for us going forward.

你在這一點上是完全正確的。事實上，我們剛啟動這項研究時，ASCO GI 就報告了第三階段研究。讓我解釋一下 20% 的門檻是從哪裡來的，以及它對我們未來的意義。

The 20% threshold was driven by the monotherapy kinase inhibitor, so the regorafenib Phase 3 study. And the our advisors, which is, as you may know, is the Academic GI Cancer Consortium, who was running that trial, said that they would like to see something upwards of maybe double of what we've seen with regorafenib alone in this patient population.

20% 的閾值是由單一療法激酶抑制劑驅動的，因此瑞格非尼 3 期研究也是如此。如您所知，我們的顧問，也就是正在進行該試驗的胃腸道癌症學術聯盟，表示他們希望看到的效果可能是我們在該患者中單獨使用瑞戈非尼時看到的效果的兩倍以上人口。

So that's where the 20% came. This is not our ceiling; this is the floor. We need to see at least something better than that to go to Phase 2, to the cohort 2.

這就是 20% 的來源。這不是我們的上限；這是地板。我們至少需要看到比這更好的東西才能進入第二階段、第二組。

A separate question that you're asking is if we just get 20% only, is this enough? Would we get excited knowing that Lonsurf and bev has a 40% PFS at months four to six. And you're right. I think the answer to that is going to be: it depends who we enrol.

您問的另一個問題是，如果我們只獲得 20%，這足夠了嗎？如果知道 Lonsurf 和 bev 在第四至六個月時的 PFS 達到​​ 40%，我們會感到興奮嗎？你是對的。我認為答案是：這取決於我們招收誰。

If we enrol patients that failed Lonsurf or Lonsurf and bev or another TPI, that would get us excited will be very different than if we have patients who really failed prior chemo immunotherapy -- I'm sorry, prior chemotherapy with bev and then they come on that study.

如果我們招募Lonsurf 或Lonsurf 和bev 或其他TPI 失敗的患者，這會讓我們感到興奮，這與我們招收之前化療免疫療法確實失敗的患者有很大不同——我很抱歉，之前用bev 進行化療，然後他們來了在那項研究上。

So I'm not trying to dodge the answer. I'm trying to say it will be determined by the kind of patient we enrol. Not unlike what David mentioned about voruciclib. If we see response in voruciclib, a progression on voruciclib, there will be -- the excitement level will be very different if we see response on -- a patient who responds to venetoclax and then progress then went back on the combination responded.

所以我並不是想迴避這個答案。我想說這將取決於我們招募的患者類型。與 David 提到的 voruciclib 沒什麼不同。如果我們看到 voruciclib 的反應，即 voruciclib 的進展，如果我們看到反應，興奮水平將會非常不同 - 一位患者對 Venetoclax 有反應，然後進展，然後又回到組合反應。

So if it's primarily driven by the patients we enrol, as is often the case in Phase 1 studies. We enrol, we look at the data, we analyze, and we make solution based on what we see.

因此，如果它主要是由我們招募的患者所驅動的，就像第一階段研究中經常出現的情況一樣。我們註冊、查看數據、分析，並根據我們所看到的解決方案。

Okay. That's helpful. And then just, lastly, I guess when you look at the 4Q R&D number implied from what you reported year end, it looks to be demonstrably down sequentially, I think sub-$3 million. How should we think about that number just going forward? And is that somehow impacted by the Kyowa transaction, some true up there? Or is that just a true number per the quarterly report and that's just going to accelerate as you guys do more clinical development here? Thanks.

好的。這很有幫助。最後，我想當你看看你年底報告中隱含的第四季度研發數字時，它看起來明顯連續下降，我認為低於 300 萬美元。我們該如何看待這個數字？這是否受到協和交易的影響，有些是真的？或者這只是季度報告中的真實數字，而隨著你們在這裡進行更多的臨床開發，這個數字只會加速？謝謝。

Yeah. It's Jay. I'll take that. So yeah, you're correct in your assessment. We're not giving specific guidance as to R&D into the next fiscal year. But I will tell you: of that, about 52.5 of R&D, about 26 of that was specifically related to zandelisib.

是的。是傑伊。我會接受的。所以是的，你的評估是正確的。我們不會就下一財年的研發提供具體指引。但我會告訴你：其中，大約 52.5 的研發，其中大約 26 與 zandelisib 特別相關。

We do know that that trial continues to wind down. We do expect that to run out at about October timeframe and probably not incur expenses any more than a million, less than that most likely. The Q4 activity is just seeing the continued wind-down of coastal and title in Q4.

我們確實知道審判仍在繼續。我們確實預計該費用將在 10 月左右用完，並且可能不會產生超過 100 萬的費用，最有可能的情況是低於這一數字。第四季度的活動剛剛看到第四季度沿海和所有權的持續減少。

And like I said, we expect that to go ahead and wind down. And then in addition to some of the other cost reductions that we've made throughout the second half of the year, overall, R&D, yeah, you're right. It will be down significantly from the prior year.

正如我所說，我們預計這種情況會繼續下去並逐漸結束。然後，除了我們在下半年所做的一些其他成本削減之外，總體而言，研發，是的，你是對的。與去年相比將大幅下降。

Okay. Thanks for taking questions.

好的。感謝您提出問題。

Sure.

當然。

Thank you.

謝謝。

This concludes our question-and-answer session. I would like to turn the conference back over to David Urso for any closing remarks.

我們的問答環節到此結束。我想將會議轉回大衛·烏爾索（David Urso）發表閉幕詞。

Thank you for joining the call today, and we appreciate your participation.

感謝您今天參加電話會議，我們感謝您的參與。

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。