MacroGenics Inc (MGNX) 2023 Q1 法說會逐字稿

Good afternoon. We will begin the MacroGenics 2023 First Quarter Corporate Progress and Financial Results Conference Call in just a moment. (Operator Instructions). At this point, I will turn the call over to Jim Karrels, Vice President, Chief Financial Officer of MacroGenics. Please go ahead.

下午好。稍後我們將開始 MacroGenics 2023 第一季度公司進展和財務業績電話會議。 （操作員說明）。在這一點上，我將把電話轉給 MacroGenics 副總裁兼首席財務官 Jim Karrels。請繼續。

Thank you, operator. Good afternoon, and welcome to MacroGenics' conference call to discuss our first quarter 2023 financial and operational results. For anyone who has not had the chance to review these results, we issued a press release this afternoon outlining today's announcements, which is available under the Investors tab on our website at macrogenics.com. You may also listen to this conference call via webcast on our website, where it will be archived for 30 days beginning approximately 2 hours after the call is completed.

謝謝你，運營商。下午好，歡迎參加 MacroGenics 的電話會議，討論我們 2023 年第一季度的財務和運營業績。對於沒有機會查看這些結果的任何人，我們今天下午發布了一份新聞稿，概述了今天的公告，可在我們網站 macrogenics.com 的“投資者”選項卡下找到。您還可以通過我們網站上的網絡廣播收聽本次電話會議，電話會議結束後約 2 小時後，該電話會議將被存檔 30 天。

I would like to alert listeners that today's discussion will include statements about the company's future expectations, plans and prospects that constitute forward-looking statements for purposes of the safe harbor provision under the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in the Risk Factors section of our annual, quarterly and current reports filed with the SEC.

我想提醒聽眾，今天的討論將包括關於公司未來預期、計劃和前景的陳述，這些陳述構成前瞻性陳述，用於根據 1995 年《私人證券訴訟改革法案》規定的安全港條款。實際結果可能與由於各種重要因素，包括我們向美國證券交易委員會提交的年度、季度和當前報告的風險因素部分中討論的那些因素，這些前瞻性陳述表明了這些因素。

In addition, any forward-looking statements represent our views only as of today. It should not be relied upon as representing our views as of any subsequent date. While we may elect to update these forward-looking statements at some point in the future, we specifically disclaim any obligation to do so even if our views change, except to the extent required by applicable law.

此外，任何前瞻性陳述僅代表我們截至今天的觀點。不應將其視為代表我們在任何後續日期的觀點。儘管我們可能會選擇在未來的某個時候更新這些前瞻性陳述，但我們明確表示，即使我們的觀點發生變化，我們也不承擔任何更新的義務，適用法律要求的範圍除外。

And now I'd like to turn the call over to Dr. Scott Koenig, President and CEO of MacroGenics.

現在我想把電話轉給 MacroGenics 總裁兼首席執行官 Scott Koenig 博士。

Thank you, Jim. I'd like to welcome everyone participating via conference call and webcast today. This afternoon I will provide key updates on our clinical programs. But before I do so, let me first turn the call back to Jim, who will review our financial results.

謝謝你，吉姆。我想歡迎今天通過電話會議和網絡廣播參與的所有人。今天下午，我將提供有關我們臨床計劃的重要更新。但在我這樣做之前，讓我先把電話轉回吉姆，他將審查我們的財務業績。

Thank you, Scott. This afternoon, MacroGenics reported financial results for the quarter ended March 31, 2023, which highlights our financial position. As described in our release this afternoon, MacroGenics total revenue consisting primarily of revenue from collaborative agreements was $24.5 million for the quarter ended March 31, 2023, compared to total revenue of $11.1 million for the quarter ended March 31, 2022. Revenue for the quarter ended March 31, 2023, included recognition of the $15 million milestone received from Incyte for the U.S. FDA approval of ZYNYZ, $3.6 million in contract manufacturing revenue and MARGENZA net sales of $3.5 million compared to $3.6 million for the quarter ended March 31, 2022.

謝謝你，斯科特。今天下午，MacroGenics 報告了截至 2023 年 3 月 31 日的季度財務業績，突出了我們的財務狀況。正如我們在今天下午發布的新聞稿中所述，截至 2023 年 3 月 31 日的季度，MacroGenics 的總收入主要包括來自合作協議的收入，為 2450 萬美元，而截至 2022 年 3 月 31 日的季度的總收入為 1110 萬美元。本季度的收入截至 2023 年 3 月 31 日，包括確認從 Incyte 收到的 1500 萬美元的里程碑，用於美國 FDA 批准 ZYNYZ 、360 萬美元的合同製造收入和 MARGENZA 淨銷售額為 350 萬美元，而截至 2022 年 3 月 31 日的季度為 360 萬美元。

Our research and development expenses were $45.9 million for the quarter ended March 31, 2023, compared to $61.4 million for the quarter ended March 31, 2022. The decrease was primarily related to decreased vobramitamab duocarmazine development costs and decreased costs related to our discontinued studies. These decreases were partially offset by increased expenses related to discovery projects and preclinical molecules and increased clinical expenses related to lorigerlimab.

截至 2023 年 3 月 31 日止的季度，我們的研發費用為 4590 萬美元，而截至 2022 年 3 月 31 日止的季度，我們的研發費用為 6140 萬美元。減少的主要原因是 vobramitamab duocarmazine 開發成本下降以及與我們停止研究相關的成本下降。這些減少被與發現項目和臨床前分子相關的費用增加以及與 lorigerlimab 相關的臨床費用增加部分抵消。

Our selling, general and administrative expenses were $13.5 million for the quarter ended March 31, 2023, compared to $16.3 million for the quarter ended March 31, 2022. The decrease was primarily related to decreased legal and consulting expenses.

截至 2023 年 3 月 31 日止的季度，我們的銷售、一般和管理費用為 1350 萬美元，而截至 2022 年 3 月 31 日止的季度為 1630 萬美元。減少主要與法律和諮詢費用減少有關。

Our net loss was $38 million for the quarter ended March 31, 2023, compared to a net loss of $66.4 million for the quarter ended March 31, 2022. Our cash, cash equivalents and marketable securities balance as of March 31, 2023, was $241.7 million compared to $154.3 million as of December 31, 2022. Our cash balance as of March 31, 2023, included the $100 million upfront payment received from a wholly owned subsidiary of DRI Healthcare Trust for the sale of our single-digit royalty and global net sales of TZIELD. Our March 31, 2023, cash balance did not include a $30 million payment subsequently received from Sanofi related to the November FDA approval milestone for TZIELD.

截至 2023 年 3 月 31 日止的季度，我們的淨虧損為 3800 萬美元，而截至 2022 年 3 月 31 日止的季度，我們的淨虧損為 6640 萬美元。截至 2023 年 3 月 31 日，我們的現金、現金等價物和有價證券餘額為 241.7 美元百萬美元，而截至 2022 年 12 月 31 日為 1.543 億美元。截至 2023 年 3 月 31 日，我們的現金餘額包括從 DRI Healthcare Trust 的全資子公司收到的 1 億美元預付款，用於出售我們的個位數特許權使用費和全球淨收入TZIELD 的銷售。我們 2023 年 3 月 31 日的現金餘額不包括隨後從賽諾菲收到的與 TZIELD 11 月 FDA 批准里程碑相關的 3000 萬美元付款。

Finally, in terms of our cash runway, we anticipate that our cash, cash equivalents and marketable securities balance of $241.7 million as of March 31, 2023, plus projected and anticipated future payments from partners and product revenues should provide us with a cash runway through 2025. Our anticipated funding requirements reflect expected expenditures related to the Phase II TAMARACK clinical trial, the Phase II portion of lorigerlimab in metastatic castration-resistant prostate cancer as well as our other clinical and preclinical studies currently ongoing.

最後，就我們的現金跑道而言，我們預計截至 2023 年 3 月 31 日我們的現金、現金等價物和有價證券餘額為 2.417 億美元，加上合作夥伴的預計和預期未來付款以及產品收入應該為我們提供一條現金跑道2025 年。我們預期的資金需求反映了與 II 期 TAMARACK 臨床試驗、lorigerlimab 在轉移性去勢抵抗性前列腺癌中的 II 期部分以及我們目前正在進行的其他臨床和臨床前研究相關的預期支出。

And now I'll turn the call back to Scott.

現在我會把電話轉回給斯科特。

Thank you, Jim. The U.S. FDA recently approved Incyte ZYNYZ or retifanlimab for the treatment of adults with metastatic or recurrent locally advanced Merkel cell carcinoma. This approval represents the third U.S. marketing clearance of our product originating from our pipeline of proprietary or partnered product candidates with MARGENZA and TZIELD being the first and second, respectively. We are delighted that the approval of ZYNYZ provides an additional option for treating patients with Merkel cell carcinoma, a rare and aggressive type of skin cancer.

謝謝你，吉姆。美國 FDA 最近批准了 Incyte ZYNYZ 或 retifanlimab 用於治療患有轉移性或複發性局部晚期 Merkel 細胞癌的成人。該批准代表我們產品的第三次美國市場許可，該產品源自我們的專有或合作候選產品管道，其中 MARGENZA 和 TZIELD 分別是第一和第二。我們很高興 ZYNYZ 的批准為治療默克爾細胞癌（一種罕見的侵襲性皮膚癌）患者提供了額外的選擇。

In addition to royalty payments for ZYNYZ and TZIELD, we remain eligible to receive more than $1 billion in milestone payments related to the continued advancement and successful commercialization of these 2 approved products. Over the past 9 months, these and other programs have allowed us to generate $270 million in nondilutive capital, extending our cash runway fully through 2025. Of course, we continue to believe our proprietary pipeline of product candidates has great promise, and I will walk you through our key programs now. Vobramitamab duocarmazine or vobra duo is our ADC designed to deliver a DNA-alkylating duocarmycin cytotoxic payload to tumors expressing B7-H3. B7-H3 is a member of the B7 family of molecules involved in immune regulation.

除了 ZYNYZ 和 TZIELD 的特許權使用費外，我們仍有資格獲得超過 10 億美元的里程碑付款，這些付款與這兩種獲批產品的持續推進和成功商業化有關。在過去的 9 個月裡，這些和其他計劃使我們能夠產生 2.7 億美元的非稀釋性資本，將我們的現金跑道完全延長到 2025 年。當然，我們仍然相信我們專有的候選產品管道有很大的希望，我會走你現在通過我們的關鍵程序。 Vobramitamab duocarmazine 或 vobra duo 是我們的 ADC，旨在為表達 B7-H3 的腫瘤提供 DNA 烷基化 duocarmycin 細胞毒性有效載荷。 B7-H3 是參與免疫調節的 B7 分子家族的成員。

Vobra duo was designed to take advantage of this antigen's broad expression across multiple solid tumor types. As we reported on our last earnings call in March, we had initiated the Phase II portion of the TAMARACK study of vobra duo in patients with metastatic castration-resistant prostate cancer in late 2022 and modified the study protocol more recently based on the changing treatment landscape for patients with metastatic castration-resistant prostate cancer.

Vobra duo 旨在利用該抗原在多種實體瘤類型中的廣泛表達。正如我們在 3 月份的上一次財報電話會議上報告的那樣，我們已於 2022 年底啟動了轉移性去勢抵抗性前列腺癌患者的 vobra duo 的 TAMARACK 研究的 II 期部分，並最近根據不斷變化的治療環境修改了研究方案適用於轉移性去勢抵抗性前列腺癌患者。

Regulatory approval of a modified study protocol primarily reflecting removal of a control arm has been obtained in the U.S. and all countries targeted for study enrollment in the E.U. We continue to anticipate commencement of enrollment under the revised protocol beginning this quarter and expect to provide a clinical update in 2024. As a reminder, the TAMARACK study is designed to evaluate vobra duo in 100 patients across 2 experimental arms, 2.0 mg/kg or 2.7 mg/kg every 4 weeks.

主要反映去除控制臂的修改後的研究方案的監管批准已在美國和所有針對歐盟研究招募的國家/地區獲得。我們繼續預計從本季度開始根據修訂後的方案開始招募，並預計將在 2024 年提供臨床更新。作為提醒，TAMARACK 研究旨在評估 2 個實驗組的 100 名患者的 vobra duo，2.0 mg/kg 或每 4 週 2.7 毫克/千克。

Next, let me update you on lorigerlimab, a bispecific, tetravalent PD-1 × CTLA-4 DART molecule. Please recall that we designed lorigerlimab to have preferential blockade on dual PD-1 CTLA-4 expressing cells, such as tumor-infiltrating lymphocytes, which are most abundant in the tumor microenvironment. At the ASCO Genitourinary Cancers Symposium in February, we presented encouraging preliminary clinical results from a single-arm dose expansion study lorigerlimab in patients with advanced solid tumors in a poster session.

接下來，讓我向您介紹 lorigerlimab，一種雙特異性、四價 PD-1 × CTLA-4 DART 分子。請回想一下，我們設計的 lorigerlimab 優先阻斷雙重 PD-1 CTLA-4 表達細胞，例如腫瘤微環境中最豐富的腫瘤浸潤淋巴細胞。在 2 月份的 ASCO 泌尿生殖系統癌症研討會上，我們在海報會議上展示了一項針對晚期實體瘤患者的單臂劑量擴展研究 lorigerlimab 的令人鼓舞的初步臨床結果。

Based on the strength of the mCRPC data presented, we plan to commence enrollment of a randomized Phase II study of lorigerlimab in combination with docetaxel versus docetaxel in second-line chemotherapy naive mCRPC patients in the second half of this year. A total of 150 patients are planned to be randomized 2:1. The current study design includes a primary study endpoint of radiographic progression-free survival.

根據所提供的 mCRPC 數據的強度，我們計劃在今年下半年開始在二線化療初治 mCRPC 患者中開展洛瑞瑪聯合多西他賽對比多西他賽的隨機 II 期研究。計劃將總共 150 名患者按 2:1 隨機分組。目前的研究設計包括放射學無進展生存期的主要研究終點。

In addition, we continue to enroll patients in the Phase I dose escalation combination study of vobra duo with lorigerlimab in patients with advanced solid tumors including renal cell carcinoma, pancreatic cancer, ovarian cancer, hepatocellular carcinoma, mCRPC and melanoma.

此外，我們繼續招募患者參加 vobra duo 與 lorigerlimab 聯合治療晚期實體瘤（包括腎細胞癌、胰腺癌、卵巢癌、肝細胞癌、mCRPC 和黑色素瘤）患者的 I 期劑量遞增聯合研究。

Next up, MGD024 is our next-generation bispecific CD123 x CD3 DART molecule that incorporates a CD3 component designed to minimize cytokine-release syndrome, while maintaining anti-tumor cytolytic activity and permitting intermittent dosing through a longer half-life. Our Phase I dose escalation study of MGD024 is ongoing in patients with CD123-positive relapsed or refractory hematologic malignancies, including acute myeloid leukemia and myelodysplastic syndromes. Recall that Gilead has the option to license MGD024 at predefined decision points during the Phase I study.

接下來，MGD024 是我們的下一代雙特異性 CD123 x CD3 DART 分子，它結合了 CD3 成分，旨在最大限度地減少細胞因子釋放綜合徵，同時保持抗腫瘤細胞溶解活性並允許通過更長的半衰期間歇給藥。我們的 MGD024 I 期劑量遞增研究正在 CD123 陽性複發性或難治性血液系統惡性腫瘤患者中進行，包括急性髓性白血病和骨髓增生異常綜合徵。回想一下，在第一階段研究期間，吉利德可以選擇在預定義的決策點許可 MGD024。

Finally, enoblituzumab is an Fc-optimized monoclonal antibody that targets B7-H3. In April, results from an investigator-sponsored Phase II study conducted at the Johns Hopkins Kimmel Cancer Center was published in Nature Medicine. In the reported study, 32 men with high-risk or very high-risk prostate cancers who are scheduled for prostate cancer surgery were treated with 6 weekly infusions of enoblituzumab prior to surgery and were followed for an average of 30 months thereafter. The sponsors reported at 21 patients or 66% had an undetectable prostate-specific antigen, PSA level 12 months following surgery, suggesting to the authors that there was no sign of residual disease. Additionally, the investigators reported that the drug was well tolerated overall; no patients had any surgical delays or medical complications during or after operation.

最後，enoblituzumab 是一種針對 B7-H3 的 Fc 優化單克隆抗體。 4 月，在約翰霍普金斯 Kimmel 癌症中心進行的一項研究者贊助的 II 期研究的結果發表在《自然醫學》上。在報告的研究中，32 名計劃接受前列腺癌手術的高危或極高危前列腺癌患者在手術前每週輸注 6 次 enoblituzumab 並在手術後平均隨訪 30 個月。贊助商報告說，有 21 名患者或 66% 的患者在手術後 12 個月無法檢測到前列腺特異性抗原和 PSA 水平，這向作者表明沒有殘留疾病的跡象。此外，研究人員報告說該藥物總體上耐受性良好；沒有患者在手術期間或手術後出現任何手術延誤或醫療並發症。

Let me next provide an update of our product candidates being developed by our collaboration partners for which we retain certain economic rights. As we previously announced, we received a $100 million upfront payment in March from DRI for the sale of our single-digit royalty on global net sales of TZIELD, while we retained the right to receive a 50% share of the royalty on global net sales above a certain annual threshold. As a result of Sanofi's acquisition of both Provention Bio and DRI's royalty interest in TZIELD in April, our economic interest are unchanged and we are eligible to receive from Sanofi a total of up to $430 million in milestone payments, including $105 million upon the achievement of certain regulatory approval milestones, $225 million upon the achievement of certain sales milestones and $100 million in potential payments from -- Sanofi assumed from DRI.

接下來讓我提供我們的合作夥伴正在開發的候選產品的最新情況，我們保留了某些經濟權利。正如我們之前宣布的那樣，我們在 3 月份收到了 DRI 的 1 億美元預付款，用於出售我們 TZIELD 全球淨銷售額的個位數特許權使用費，同時我們保留獲得全球淨銷售額特許權使用費 50% 份額的權利超過一定的年度門檻。由於賽諾菲在 4 月份收購了 Provention Bio 和 DRI 在 TZIELD 的特許權使用費權益，我們的經濟利益沒有改變，我們有資格從賽諾菲獲得總計高達 4.3 億美元的里程碑付款，其中包括 1.05 億美元在實現某些監管批准里程碑，實現某些銷售里程碑後的 2.25 億美元和來自 DRI 的賽諾菲（Sanofi）承擔的 1 億美元潛在付款。

Also, as previously announced in March, the FDA approved ZYNYZ, a humanized monoclonal antibody targeting PD-1. We had initially developed this molecule and licensed it to Incyte in October 2017, pursuant to an exclusive global collaboration and license agreement. Incyte continues to conduct global registration studies of retifanlimab across multiple indications, including lung, anal and endometrial cancer. Under our amended agreement with Incyte, we received a $15 million milestone payment from Incyte based on the approval of ZYNYZ in Merkel cell carcinoma during the first quarter of 2023, and are eligible to receive up to $320 million of potential remaining development and regulatory milestones and up to $330 million in potential commercial milestones. We were also eligible to receive tiered royalties of 15% to 24% from Incyte on any global net sales of the product. Finally, we will manufacture a portion of Incyte's global commercial supply of retifanlimab.

此外，正如之前在 3 月份宣布的那樣，FDA 批准了 ZYNYZ，這是一種針對 PD-1 的人源化單克隆抗體。根據獨家全球合作和許可協議，我們最初開發了這種分子，並於 2017 年 10 月將其授權給 Incyte。 Incyte 繼續在多個適應症（包括肺癌、肛門癌和子宮內膜癌）中開展 retifanlimab 的全球註冊研究。根據我們與 Incyte 的修訂協議，我們在 2023 年第一季度根據默克爾細胞癌中 ZYNYZ 的批准從 Incyte 收到了 1500 萬美元的里程碑付款，並且有資格獲得高達 3.2 億美元的潛在剩餘開發和監管里程碑和高達 3.3 億美元的潛在商業里程碑。我們還有資格從 Incyte 獲得產品任何全球淨銷售額的 15% 至 24% 的分級特許權使用費。最後，我們將製造因塞特公司全球商業供應的一部分 retifanlimab。

To conclude, we believe we have shown that we have the technical development and clinical expertise and now the necessary financial resources to support execution on our plan of developing and delivering life-changing medicines to cancer patients in 2023 and beyond. We would now be happy to open the call for questions. Operator?

總而言之，我們相信我們已經證明我們擁有技術開發和臨床專業知識，現在還有必要的財政資源來支持執行我們在 2023 年及以後為癌症患者開發和提供改變生命的藥物的計劃。我們現在很樂意打開問題電話。操作員？

(Operator Instructions) Our first question comes from the line of Jonathan Chang with SVB Securities.

（操作員說明）我們的第一個問題來自 SVB 證券公司的 Jonathan Chang。

First question on cash position. How are you guys thinking about your cash position now following the non-dilutive deals you've completed over the past 9 months. At this point, do you feel you have enough to execute on your plans until the value inflection point? And are you still actively seeking opportunities to continue bolstering your balance sheet?

關於現金狀況的第一個問題。在你們過去 9 個月完成的非稀釋性交易之後，你們現在如何看待你們的現金狀況。在這一點上，你覺得你有足夠的時間來執行你的計劃直到價值拐點嗎？您是否仍在積極尋找機會繼續鞏固資產負債表？

Nice to hear from you, Jonathan. So we're very pleased, obviously, with our cash position. And as stated on the call, this will take us through 2025 into early 2026. And yes, this has all the opportunities to execute on the plan that we have outlined and the programs that we discussed today. And potentially looking at additional opportunities, especially in prostate cancer and beyond in solid tumors. Of course, as you know, we have been always very active in business development activities and have continuous ongoing discussions, both in terms of our preclinical and clinical pipelines, and we anticipate in the future that further revenues could be accrued the successful execution of those business deals.

很高興收到你的來信，喬納森。因此，我們顯然對我們的現金狀況感到非常滿意。正如電話會議上所述，這將使我們從 2025 年到 2026 年初。是的，這有所有機會來執行我們概述的計劃和我們今天討論的計劃。並有可能尋找更多機會，尤其是在前列腺癌和實體瘤以外的領域。當然，如您所知，我們一直非常積極地參與業務發展活動，並就我們的臨床前和臨床管道進行持續的討論，我們預計未來可以通過成功執行這些項目獲得更多收入商業交易。

Got it. And second question, should we expecting clinical data from the vobra duo plus lorigerlimab combo study this year? And if so, could you help set expectations ahead of that update?

知道了。第二個問題，我們是否應該期待今年 vobra duo 加 lorigerlimab 組合研究的臨床數據？如果是這樣，你能幫助設定更新之前的期望嗎？

So as I had mentioned on earlier calls, we've been moving forward with identifying the proper dosing for individual components in that combination and obviously open up the study to 6 different tumor indications to participate in the study. We have not yet settled on the specific dose to move forward in expansion studies and would anticipate once that is achieved, we would move forward in 1 or 2 expansion studies of particular indications, which I expect would probably include prostate and one and possibly another. At this point, given where we are this year, it is less likely that we will have data by the end of this year and more likely in the first part of 2024.

因此，正如我在之前的電話會議上提到的那樣，我們一直在推進確定該組合中各個成分的正確劑量，並且顯然將研究開放給 6 種不同的腫瘤適應症以參與該研究。我們尚未確定在擴展研究中推進的具體劑量，預計一旦實現，我們將推進 1 或 2 個特定適應症的擴展研究，我預計這可能包括前列腺和一個，也可能是另一個。在這一點上，鑑於我們今年的情況，我們不太可能在今年年底之前獲得數據，而在 2024 年上半年獲得數據的可能性更大。

Our next question comes from the line of Charles Zhu with Guggenheim.

我們的下一個問題來自 Charles Zhu 與 Guggenheim 的對話。

This is Edouard on for Charles Zu. Maybe just a question on the lorigerlimab/ doletaxel combo trial that you're looking towards. What sort of efficacy signal would you anticipate from the docetaxel control arm? And what sort of efficacy signal in the combo arm would give you confidence in the combination going forward? And that's both with respect to the control arm, but also with respect to the broader competitive landscape in the chemo naive setting?

這是 Charles Zu 的 Edouard。也許只是關於您正在尋找的 lorigerlimab/doletaxel 組合試驗的問題。您預計多西紫杉醇對照組會產生什麼樣的療效信號？組合臂中什麼樣的療效信號會讓您對組合的未來充滿信心？這既是關於控制臂，也是關於化療天真的環境中更廣泛的競爭格局？

So thanks for the questions, Edouard. So if you look at the historical data of the docetaxel control arms, in patients who have progressed on [ARAD] agents, rPFS has been consistent across the board with KEYNOTE-921 preside the Phase IIIb and TRITON3 of 8.3 months and median overall survival of 19 and 18.9, respectively, in 921 and TRITON3. So obviously, we would like to exceed those -- certainly meet them, but certainly exceed them with the current study. And obviously, longer is better in this case.

謝謝你的問題，Edouard。因此，如果您查看多西他賽對照組的歷史數據，在使用 [ARAD] 藥物取得進展的患者中，rPFS 與 KEYNOTE-921 主持的 IIIb 期和 TRITON3 為 8.3 個月，中位總生存期為在 921 和 TRITON3 中分別為 19 和 18.9。很明顯，我們希望超越這些 - 當然會達到它們，但肯定會通過當前的研究超過它們。顯然，在這種情況下，時間越長越好。

And then maybe just as a follow-up. So what are your -- how are you seeing the sort of the competitive landscape shaping up in the chemo-naive setting again with PSMA4 we know it hits that big. So just kind of how you're thinking about it there and how you see the combo fitting in?

然後也許只是作為後續行動。那麼你是什麼——你如何看待 PSMA4 再次在化學天真的環境中形成的那種競爭格局，我們知道它會產生如此大的影響。那麼，您是如何考慮它的，以及您如何看待組合的適應性？

Well, I mean, clearly, the historical data on checkpoints in -- first of all, in prostate in general or prostate, certainly in that line of setting has been dismal. If you look at all the studies that have been conducted with pembrolizumab, including KEYLYNK-010, KEYNOTE-921, 991 and 641, they did not meet the expected outcomes, even though those are in different lines of therapy and different combinations. And as you know from the recent data on CheckMate 650, with a combination of nivolumab and ipilimumab, the responses at nivolumab 3, ipi 1 were not good with a 9.3% overall response rate in the PSA 50 of 13.8%. So we think that we have an unusual molecule now as a bispecific to introduce a checkpoint molecule on top of standard therapy that could really change the course of this disease.

好吧，我的意思是，很明顯，關於檢查點的歷史數據——首先，在一般前列腺或前列腺中，當然在那種情況下，檢查站的歷史數據一直很糟糕。如果您查看所有使用 pembrolizumab 進行的研究，包括 KEYLYNK-010、KEYNOTE-921、991 和 641，它們都沒有達到預期的結果，即使這些研究採用不同的治療方案和不同的組合。正如您從 CheckMate 650 的最新數據中了解到的那樣，聯合使用 nivolumab 和 ipilimumab，nivolumab 3、ipi 1 的反應並不好，總體反應率為 9.3%，PSA 50 為 13.8%。所以我們認為我們現在有一個不尋常的分子作為雙特異性分子在標準療法之上引入一個檢查點分子，這可能真正改變這種疾病的進程。

Our next question comes from the line of Yigal Nochomovitz with Citi.

我們的下一個問題來自花旗的 Yigal Nochomovitz。

This is [Ashik Mubarak] on for Yigal. Maybe just asking another one on lorigerlimab. I think in the past you alluded to the idea of lowering the lorigerlimab dose as a way to better manage AEs, but still have full target engagement. I guess within that context, how are you thinking about dosing for the docetaxel cohort -- combo and cohort you're planning on starting to operate shortly? Are there any specific comments you can make on the lorigerlimab dose in that combo?

這是 [Ashik Mubarak] 替 Yigal 上場。也許只是問另一個關於 lorigerlimab 的問題。我想在過去你提到了降低 lorigerlimab 劑量的想法，作為更好地管理 AE 的一種方式，但仍然有完整的目標參與。我想在這種情況下，您如何考慮多西紫杉醇隊列的劑量 - 您計劃很快開始運作的組合和隊列？您對該組合中的 lorigerlimab 劑量有什麼具體的評論嗎？

Yes. Thank you very much for the question. And as you've noted before -- noted, we have a very robust data set from our dose escalation and expansion studies where in our dose escalation we went up to 10 mg/kg without dose-limiting toxicity, designed the study on expansion at 6 mg/kg on a Q3 weekly basis, in over -- in 127 patients, which we presented recently at the ASCO GU meeting.

是的。非常感謝你的提問。正如您之前提到的那樣——注意到，我們從劑量遞增和擴展研究中獲得了非常可靠的數據集，在我們的劑量遞增中，我們達到了 10 mg/kg 而沒有劑量限制性毒性，設計了擴展研究我們最近在 ASCO GU 會議上介紹了超過 127 名患者，每週 3 季度 6 mg/kg。

As we have pointed out previously, we get full occupancy of PD-1 receptor and 1 mg/kg or higher and have historically shown in the dose escalation study of lorigerlimab objective responses at 3 mg/kg and also at 6 mg/kg. And we were seeing biomarker data of expansion both CD4 and CD8 at 1 mg/kg or higher as well as the induction of IQOS in CD4 positive cells in the similar ranges. So we have a very wide window of opportunity to adjust treatment doses based on either combinations of drugs that may add on additional toxicities.

正如我們之前指出的那樣，我們得到了 PD-1 受體的完全佔用和 1 mg/kg 或更高，並且歷史上已經在 3 mg/kg 和 6 mg/kg 的 lorigerlimab 客觀反應的劑量遞增研究中顯示。我們看到了 CD4 和 CD8 以 1 mg/kg 或更高濃度擴增的生物標誌物數據，以及類似範圍內 CD4 陽性細胞中 IQOS 的誘導。因此，我們有很大的機會根據可能增加額外毒性的藥物組合來調整治療劑量。

So back to your initial question, we are starting at 6 mg/kg on a Q3 weekly basis. We had the opportunity to make adjustments. And we're also looking at potential future studies where we would study more than the 6 mg/kg dose in prostate cancer or potentially other tumors as well to get the best safety and efficacy profile for the drug.

回到你最初的問題，我們開始每週 6 毫克/千克。我們有機會做出調整。我們也在研究潛在的未來研究，我們將在前列腺癌或其他潛在腫瘤中研究超過 6 mg/kg 的劑量，以獲得該藥物的最佳安全性和有效性。

Got it. If I could ask one more on vobra duo. I guess we're still waiting for the TAMARACK data before it ultimately make any ultimate decision. But do you have any updated thoughts on how you're thinking about vobra duo as a monotherapy within prostate cancer? I think, maybe once we have clarity on the treatment paradigm, maybe within the coming years, do you -- have you -- is there a possibility you would reconsider a pivotal trial with just the monotherapy?

知道了。如果我能再問一個關於 vobra duo 的問題。我想在它最終做出任何最終決定之前，我們仍在等待 TAMARACK 數據。但是，對於如何將 vobra duo 作為前列腺癌的單一療法，您是否有任何最新的想法？我認為，也許一旦我們明確了治療範式，也許在未來幾年內，您是否有可能重新考慮僅使用單一療法的關鍵試驗？

Absolutely. I mean I think the current plan right now was just taking the realization of the time to enrollment where we made the amendments to the protocol of TAMARACK to remove the control group. The idea of this study right now is to execute as quickly as possible. So we were able to decide both on the safety and the activity what is the appropriate dose, either the 2 mg/kg Q4 or the 2.7 mg/kg Q4. At that point, we would go into a -- our plan would be if we achieve the goals that we set for that study to go into a single-arm study moving forward in Phase III. And clearly, obviously, we're exploring the opportunity of combining it with other active agents, given as was discussed earlier, the combination with lorigerlimab, but we're also looking at other combinations potentially in the future.

絕對地。我的意思是，我認為目前的計劃只是利用時間來實現我們對 TAMARACK 協議進行修改以刪除對照組的註冊時間。目前這項研究的想法是盡快執行。因此，我們能夠根據安全性和活性來決定合適的劑量是 2 mg/kg Q4 還是 2.7 mg/kg Q4。到那時，我們將進入一個——我們的計劃是，如果我們實現我們為該研究設定的目標，進入第三階段的單臂研究。很明顯，很明顯，我們正在探索將它與其他活性藥物結合的機會，正如之前討論的那樣，與 lorigerlimab 的結合，但我們也在尋找未來可能的其他組合。

Our next question comes from the line of Kaveri Pohlman with BTIG.

我們的下一個問題來自 BTIG 的 Kaveri Pohlman。

Congrats on the approval of ZYNYZ. For the Phase II trial with docetaxel for lorigerlimab, can you provide any additional color on your development strategy? Can you maybe go for a registration-enabling trial if let's say the interim analysis looks positive given the big size of the study.

恭喜 ZYNYZ 獲得批准。對於多西紫杉醇用於 lorigerlimab 的 II 期試驗，您能否為您的開發策略提供任何額外的顏色？如果考慮到研究的規模很大，我們可以說中期分析看起來是積極的，你是否可以進行允許註冊的試驗。

Yes, that's an excellent question. And obviously, this is designed as a controlled study 2:1, but given that this is only 150 patients, we do not expect that this study alone would be sufficient to meet the regulatory requirements for an approval and would then base the successful study to expand that into a full Phase III study, obviously, great overarching data [trumps all], but right now, we don't intend that this study would serve as a trial for approval.

是的，這是一個很好的問題。顯然，這是一項 2:1 的對照研究，但鑑於這只有 150 名患者，我們預計僅這項研究不足以滿足批准的監管要求，然後將成功的研究建立在將其擴展為完整的 III 期研究，顯然，重要的總體數據[勝過一切]，但現在，我們不打算將這項研究作為批准試驗。

All right. That's helpful. And my second question is also on lorigerlimab. So based on KEYNOTE-199 and CheckMate 650 trial results, it seems like CD1 x CTLA-4 combination is more active than PD-1 alone. Any thoughts on going into MSI high CRPC prostate cancer as monotherapy? Is it commercially attractive? And similarly, does the combination of PARP inhibitors make sense because CheckMate 650 trials showed better efficacy in HRD-positive patients.

好的。這很有幫助。我的第二個問題也是關於 lorigerlimab 的。因此，根據 KEYNOTE-199 和 CheckMate 650 試驗結果，CD1 x CTLA-4 組合似乎比單獨的 PD-1 更活躍。關於將 MSI 高 CRPC 前列腺癌作為單一療法進行治療有什麼想法嗎？它具有商業吸引力嗎？同樣，PARP 抑製劑的組合是否有意義，因為 CheckMate 650 試驗在 HRD 陽性患者中顯示出更好的療效。

Excellent questions. So answering your question, obviously, responding and I agree with you based on the 199 study and the 650 study, and the data that we have shown at ASCO GU in terms of a 26% objective response rate and over 90% PSA 50 and all responding patients had actually greater than PSA 90 responses that we're in a very good position with this molecule to move it forward.

很好的問題。所以回答你的問題，很明顯，根據 199 項研究和 650 項研究，以及我們在 ASCO GU 上顯示的數據，客觀回應率為 26%，PSA 50 超過 90% 等等，我同意你的看法有反應的患者實際上有超過 PSA 90 的反應，我們在這個分子上處於非常有利的位置，可以推動它向前發展。

With regard to MSI high, we have not set up a trial that's something we could consider. We certainly are looking at additional combinations and given that the treatment regimens for prostate cancer are revolving with the use of PARP inhibitors even in early line therapy without DNA repair defects. We would consider additional combination sides of the future, but have nothing right now that would incorporate this in our current studies.

關於 MSI high，我們還沒有建立一個我們可以考慮的試驗。我們當然正在研究其他組合，並且考慮到前列腺癌的治療方案正在使用 PARP 抑製劑，即使在沒有 DNA 修復缺陷的早期線治療中也是如此。我們會考慮未來的其他組合方面，但現在沒有任何東西可以將其納入我們當前的研究。

That's helpful. And maybe a last one on ADC. Since we're waiting for the updated data, but do you plan to show any mature data from the Phase I trial, I believe, from the last readout in 2021, the sample size was decent for the patients who remained on treatment.

這很有幫助。也許是關於 ADC 的最後一個。由於我們正在等待更新的數據，但您是否打算展示 I 期試驗的任何成熟數據，我相信，從 2021 年的最後一次讀數開始，樣本量對於仍在接受治療的患者來說是合適的。

Yes. As we've noted on previous calls, we've had objective response rates in all the tumor types that we looked at and had historically considered actually studying additional patients after prostate cancer and melanoma. But because at that time, we did not have the cash runway to justify moving forward with that, we stopped that planned study. What I have said in previous calls is that we will provide data at times when we start or plan to initiate studies in additional indications and not until then.

是的。正如我們在之前的電話會議上指出的那樣，我們在我們研究的所有腫瘤類型中都有客觀的反應率，並且在歷史上考慮過在前列腺癌和黑色素瘤之後實際研究更多的患者。但是因為當時我們沒有足夠的資金來證明繼續進行這項工作，所以我們停止了計劃中的研究。我在之前的電話中說過，我們將在開始或計劃啟動其他適應症的研究時提供數據，但直到那時才提供。

I would also like -- let me just also add a comment from the earlier call that when I was discussing the treatment in the lorigerlimab study that I was talking about a single agent, not a single-arm study. So just to make sure that people were not confused by my statement.

我還想——讓我也補充一下之前電話會議的評論，當我在討論 lorigerlimab 研究中的治療時，我談論的是單一藥物，而不是單臂研究。所以只是為了確保人們不會對我的陳述感到困惑。

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

我們的下一個問題來自 Stifel 的 Stephen Willey。

So I know you've done a couple of licensing deals here just to gain access to some novel linker payload technology. And I guess -- just wondering how that preclinical work is progressing, whether you're specifically focused on [TOPO1] derivatives, which is, I guess, kind of seen where the entire landscape is tilting right now. And whether the added balance sheet strength now allows you to accelerate some of those development efforts going forward?

所以我知道你在這裡做了一些許可交易，只是為了獲得一些新穎的鏈接器有效負載技術。我想——只是想知道臨床前工作的進展情況，你是否特別關注 [TOPO1] 衍生物，我想，這是現在整個景觀正在傾斜的地方。現在增加的資產負債表實力是否允許您加快其中一些開發工作的進展？

Great question, Steve. And as you know, we've been very high on the opportunities that have been afforded us by these additional licensing deals with Sinafix, originally having access to 3 linker toxin combinations for specific targets that we expanded before additional targets, so 7 and all.

好問題，史蒂夫。正如你所知，我們一直非常重視與 Sinafix 的這些額外許可交易為我們提供的機會，最初可以訪問 3 個鏈接器毒素組合，用於我們在其他目標之前擴展的特定目標，所以 7 個和所有。

The preclinical development is going exceptionally well, as we've pointed out on earlier call, we intend to file an IND in the fourth quarter this year with the first of these new agents. And at this point, it's all forward on the next one. And again, without getting precision here, we're trying to target for late '24 for the second one as we're building additional molecules going forward. You should be assured that many of these molecules will include a [topoisomerase leukotoxin] opportunity.

正如我們在早些時候的電話會議上指出的那樣，臨床前開發進展非常順利，我們打算在今年第四季度使用這些新藥物中的第一個提交 IND。在這一點上，一切都在下一個。再一次，在這裡沒有得到精確度，我們正試圖將第二個目標定在 24 年底，因為我們正在構建更多的分子。您應該放心，這些分子中的許多將包含 [拓撲異構酶白細胞毒素] 機會。

Our next question comes from the line of [Shay Simi] with Barclays.

我們的下一個問題來自 [Shay Simi] 與 Barclays 的對話。

This is Shay on for Peter Lawson. Maybe first, just quickly on the vobra duo and lorigerlimab combo. It sounds like you're still finding the right go-forward dose here, maybe that is not until 2024. But could you give a little more color on what's built into there? Is that the room to go dose escalate higher? Or is this more about finding the right balance from a safety perspective?

這是 Peter Lawson 的 Shay on。也許首先，快速使用 vobra duo 和 lorigerlimab 組合。聽起來您仍在尋找合適的前進劑量，也許要到 2024 年。但是您能為其中的內置內容提供更多顏色嗎？這是劑量升級的空間嗎？或者這更多是為了從安全角度找到合適的平衡點？

Excellent question, Shay. And as noted before, we want to have the -- both combinations that give the safety and activity that we think that can be achieved in both an additive or a potential synergistic way. And so we could envision that these could be both -- in terms of, let's say, lorigerlimab, which we start at 6 mg/kg, we didn't expect to go higher on lorigerlimab. So the opportunity was to keep that or going lower.

很好的問題，謝伊。如前所述，我們希望擁有——這兩種組合都能提供我們認為可以通過添加劑或潛在協同方式實現的安全性和活性。因此，我們可以設想這些可能是兩者——比如說，我們從 6 mg/kg 開始的 lorigerlimab，我們沒想到 lorigerlimab 會更高。因此，機會是保持這一點或走低。

And the same story with vobra as you know, we are exploring 2.0 mg/kg or 2.7 mg/kg in the current study. And given the potential here for synergy here on activity, there is also an opportunity that you may be able to even lower the doses from the historical use of this drug at 3 mg/kg. And as you know, we started initially at 1 mg/kg in the first cohort going forward. So where we end up at this point, we don't know. And until we have that precision, we won't go forward into the expansion studies.

正如您所知，與 vobra 的故事相同，我們在當前研究中正在探索 2.0 mg/kg 或 2.7 mg/kg。考慮到這裡對活動的協同作用的潛力，你也有機會甚至可以將這種藥物的歷史使用劑量降低到 3 mg/kg。如您所知，我們最初在第一批隊列中以 1 mg/kg 開始。所以我們現在在哪裡結束，我們不知道。在我們達到這種精確度之前，我們不會繼續進行擴展研究。

That's helpful. And just a last quick question. Considering the removal of the control arm for vobra duo and prostate, I guess how are you thinking now about your registrational strategy moving forward?

這很有幫助。最後一個簡單的問題。考慮到去除 vobra duo 和前列腺的控制臂，我想您現在如何考慮您的註冊策略？

As you know, this is a changing landscape where we sit right now with (inaudible) coming on board recently, we want to see how far that use of that drug is and in various lines of therapy, we want to see other combinations that was brought up earlier on this call about the use of PARP inhibitors. So what we are right now going to look at the landscape when we've completed and selected the doses for vobra going forward, and we'll see what the appropriate control. One can envision a specific control or one of several that investigators get to choose from, but we're right not ready yet to make that decision.

如您所知，這是一個不斷變化的格局，我們現在坐在那裡（聽不清）最近加入，我們想看看這種藥物的使用有多遠以及在各種治療方面，我們想看看其他組合早些時候在本次電話會議上提到了 PARP 抑製劑的使用。因此，當我們完成並選擇未來的 vobra 劑量後，我們現在要看的是什麼，我們將看到什麼是適當的控制。人們可以設想一個特定的控製或調查人員可以從中選擇的幾個控制之一，但我們還沒有準備好做出那個決定。

Thank you. I would like to turn the conference back over to Jim Karrels for any further closing remarks.

謝謝。我想將會議轉回 Jim Karrels 以作任何進一步的閉幕詞。

Thank you, operator. This is Scott Koenig. I want to thank everybody who participated in this call today. We appreciate and look forward to updating you on our future studies on the next call.

謝謝你，運營商。我是斯科特·科尼格。我要感謝今天參加這個電話會議的每一個人。我們感謝並期待在下一次電話會議上向您更新我們未來的研究。

This concludes today's conference call. Thank you for participating. You may now disconnect.

今天的電話會議到此結束。感謝您的參與。您現在可以斷開連接。