Cardiff Oncology Inc (CRDF) 2017 Q1 法說會逐字稿

Welcome to Trovagene's First Quarter 2017 Earning Results Conference Call and Webcast. All participants will be in listen-only mode. (Operator Instructions). Please also note that this event is being recorded.

歡迎參加 Trovagene 2017 年第一季度盈利結果電話會議和網絡廣播。所有參與者都將處於僅聽模式。 （操作員說明）。另請注意，該事件正在被記錄。

I would now like to turn the conference call over to Ms. Vicki Kelemen, Senior Director of Communications. Ms. Kelemen, please go ahead.

我現在想將電話會議轉交給高級傳播總監 Vicki Kelemen 女士。凱萊門女士，請繼續。

Thank you for joining us today on our first quarter 2017 conference call. Joining me today are Bill Welch, Chief Executive Officer; and Mark Erlander, Chief Scientific Officer.

感謝您今天參加我們的 2017 年第一季度電話會議。今天與我一起出席的是首席執行官比爾·韋爾奇 (Bill Welch)；馬克·埃蘭德（Mark Erlander），首席科學官。

Before I turn the call over to Bill, I must remind you of the risks inherent in our business and ask you to consider the following forward-looking statements. Certain statements in this call are forward-looking within the meaning of the Private Securities Litigation Reform Act of 1995. These statements may be identified by the use of words such as anticipate, believe, forecast, estimated and intend or other similar terms or expressions that concern Trovagene's expectations, strategy, plans or intentions. These forward-looking statements are based on Trovagene's current expectations and actual results could differ materially. There are a number of factors that could cause actual events to differ materially from those indicated by such forward-looking statements. Investors should read the risk factors set forth in Trovagene's Form 10-K for the year ended December 31, 2016, and other periodic reports filed with the Securities and Exchange Commission. While the list of factors presented in the 10-K is considered representative, no such list should be considered to be a complete statement of all potential risks and uncertainties. Unlisted factors may present significant additional obstacles to the realization of forward-looking statements. Forward-looking statements included herein are made as of date hereof and Trovagene does not undertake any obligation to update publicly such statements to reflect subsequent events or circumstances.

在我將電話轉給比爾之前，我必須提醒您我們業務固有的風險，並請您考慮以下前瞻性陳述。本次電話會議中的某些陳述具有 1995 年《私人證券訴訟改革法案》含義內的前瞻性陳述。這些陳述可以通過使用“預期”、“相信”、“預測”、“估計”和“打算”等詞語或其他類似術語或表達來識別。關注 Trovagene 的期望、戰略、計劃或意圖。這些前瞻性陳述基於 Trovagene 當前的預期，實際結果可能存在重大差異。有許多因素可能導致實際事件與此類前瞻性陳述所表明的情況存在重大差異。投資者應閱讀 Trovagene 截至 2016 年 12 月 31 日止年度的 10-K 表格以及向美國證券交易委員會提交的其他定期報告中列出的風險因素。雖然 10-K 中列出的因素被認為具有代表性，但此類列表不應被視為對所有潛在風險和不確定性的完整陳述。未列出的因素可能會給前瞻性陳述的實現帶來重大的額外障礙。本文中包含的前瞻性陳述是截至本文發布之日作出的，Trovagene 不承擔任何公開更新此類陳述以反映後續事件或情況的義務。

With that, I would now like to turn the call over to our Chief Executive Officer, Bill Welch. Bill?

現在，我想將電話轉給我們的首席執行官比爾·韋爾奇。賬單？

Thanks, Vicki. Hello, everyone, and thank you for joining us today. I will begin today's call with a brief update on our progress since announcing the licensing of PCM-075, a polo-like kinase 1 or PLK1 inhibitor, which we are developing for the treatment of acute myeloid leukemia or AML. Mark will share additional details regarding our PCM-075 clinical development plans and next steps. Afterwards, I will provide an overview of our financial results for the first quarter of 2017 as well as closing remarks.

謝謝，維基。大家好，感謝您今天加入我們。在今天的電話會議中，我將首先簡要介紹自宣布 PCM-075 獲得許可以來取得的進展，PCM-075 是一種 Polo 樣激酶 1 或 PLK1 抑製劑，我們正在開發該藥物用於治療急性髓系白血病或 AML。 Mark 將分享有關我們的 PCM-075 臨床開發計劃和後續步驟的更多詳細信息。隨後，我將概述 2017 年第一季度的財務業績並作閉幕致辭。

We are excited about advancing our business in precision medicine and the development of precision cancer therapeutics for improved cancer care. PCM-075 allows us to leverage our precision cancer monitoring technology and expertise in tumor genomics to optimize the clinical development process and uniquely positions us to bring a first-in-class PLK1 to market for the treatment of patients with AML. AML is a cancer of blood cells and is characterized by the rapid growth of abnormal white blood cells that buildup in the bone marrow and blood. While AML is a relatively rare disease, the risk for AML increases with age, and its incidence is expected to grow as the population ages. AML has a five-year survival rate of approximately 25%. Current treatments include an intensive chemotherapy regimen that has been used for over 40 years, and for younger patients, stem cell transplantation as it can be prohibitively toxic for older patients. Consequently, there is a significant opportunity for new treatment options.

我們很高興能夠推進我們在精準醫療領域的業務以及開發精準癌症療法以改善癌症護理。 PCM-075 使我們能夠利用我們的精準癌症監測技術和腫瘤基因組學方面的專業知識來優化臨床開發流程，並使我們處於獨特的地位，能夠將一流的 PLK1 推向市場，用於治療 AML 患者。 AML 是一种血細胞癌症，其特徵是骨髓和血液中積聚的異常白細胞快速生長。雖然 AML 是一種相對罕見的疾病，但 AML 的風險隨著年齡的增長而增加，並且其發病率預計會隨著人口老齡化而增加。 AML 的五年生存率約為 25%。目前的治療方法包括已使用 40 多年的強化化療方案，以及針對年輕患者的干細胞移植，因為它對老年患者可能具有令人望而卻步的毒性。因此，新的治療選擇存在重大機會。

Our interest in AML and PCM-075 stem from favorable preclinical and Phase 1 data, improved bioavailability and the potential for a more selective therapeutic approach. We believe PCM-075 can improve on past clinical studies conducted with the pan polo-like kinase inhibitor. This class drug candidate demonstrated increased response rates and improved overall survival in AML patients in the Phase II studies, but did not reach the primary endpoint in its Phase III trial, likely due to infections. Unlike this pan polo-like kinase inhibitor, PCM-075 targets only PLK1, has a five-time shorter half-life and is administered orally, not intravenously. Mark will provide more details on our PCM-075 clinical development pathway. We believe that PCM-075 can be a safer, more efficacious polo-like kinase inhibitor for the treatment of AML with a potential to be used to treat other hematologic and solid tumor cancers. We plan to use our expertise and proprietary diagnostic technology to develop a PCM-075 AML biomarker panel so that we can identify patients most likely to respond to therapy and measure their response.

我們對 AML 和 PCM-075 的興趣源於良好的臨床前和 1 期數據、改善的生物利用度以及更具選擇性的治療方法的潛力。我們相信 PCM-075 可以改進過去使用泛馬球樣激酶抑製劑進行的臨床研究。此類候選藥物在 II 期研究中證明了 AML 患者的緩解率有所提高並改善了總體生存率，但在 III 期試驗中並未達到主要終點，可能是由於感染。與這種泛馬球樣激酶抑製劑不同，PCM-075 僅針對 PLK1，半衰期短五倍，並且是口服給藥，而不是靜脈注射。 Mark 將提供有關我們的 PCM-075 臨床開發途徑的更多詳細信息。我們相信PCM-075可以成為一種更安全、更有效的polo樣激酶抑製劑，用於治療AML，並有可能用於治療其他血液學和實體瘤癌症。我們計劃利用我們的專業知識和專有診斷技術來開發 PCM-075 AML 生物標誌物組，以便我們能夠識別最有可能對治療產生反應的患者並測量他們的反應。

We see a number of value drivers in 2017 with our precision medicine programs, including FDA acceptance of our Phase 1/2 clinical trial protocol for PCM-075 in patients with AML; the development of an AML genetic marker panel to better assess patients' response to therapies; the publication of a manuscript on PCM-075 Phase 1 safety study in solid tumors and presentation of PCM-075 preclinical data in AML and other hematological cancers at key conferences; the execution of commercial development programs that generate over $1 million in revenue from clinical testing services, licensing and research kit sales; the product rollout of NextCollect, our universal urine collection and DNA preservation system to pharmaceutical and research laboratories for initial sales; and the first PCM-075 annual patient enrolled in our Phase 1/2 clinical trial.

2017 年，我們的精準醫療計劃帶來了許多價值驅動因素，包括 FDA 接受我們針對 AML 患者的 PCM-075 1/2 期臨床試驗方案；開發 AML 遺傳標記物組，以更好地評估患者對治療的反應；發表關於 PCM-075 實體瘤 1 期安全性研究的手稿，並在重要會議上介紹 PCM-075 在 AML 和其他血液癌症中的臨床前數據；執行商業開發計劃，從臨床測試服務、許可和研究套件銷售中產生超過 100 萬美元的收入；向製藥和研究實驗室推出我們的通用尿液採集和 DNA 保存系統 NextCollect 產品以進行首次銷售；第一位 PCM-075 年度患者參加了我們的 1/2 期臨床試驗。

I am pleased to announce that we've entered into two separate agreements with the large international pharmaceutical companies to provide our CLIA/CAP-accredited tests and laboratory testing services. Both companies plan to use our Trovera liquid biopsy tests as biomarkers to evaluate patients' response to therapy in their clinical studies. We anticipate performing CLIA laboratory testing programs with other clinical research third parties. We are collecting revenue from private and government payers for Trovera tests performed in 2016, and we continue to provide access to our test for physicians and their patients. We believe these activities are accretive to Trovagene and should provide positive contributions to the company and will help fund our precision therapeutics program.

我很高興地宣布，我們已與大型國際製藥公司簽訂了兩項單獨的協議，以提供我們的 CLIA/CAP 認可的測試和實驗室測試服務。兩家公司都計劃使用我們的 Trovera 液體活檢測試作為生物標誌物，以評估患者在臨床研究中對治療的反應。我們預計與其他臨床研究第三方一起執行 CLIA 實驗室測試項目。我們正在向私人和政府付款人收取 2016 年進行的 Trovera 測試的收入，並且我們將繼續為醫生及其患者提供使用我們的測試的機會。我們相信這些活動能夠為 Trovagene 帶來增值，應該為公司做出積極貢獻，並將有助於為我們的精準治療項目提供資金。

We plan to launch NextCollect in the second quarter for research use by academic institutions and laboratories. NextCollect simplifies the urine collection process and optimizes the preservation of DNA. It is designed to be a cost-effective alternative to bio -- to blood-based DNA collection tubes and has potentially broad-based applications in oncology and beyond.

我們計劃在第二季度推出 NextCollect，供學術機構和實驗室研究使用。 NextCollect 簡化了尿液收集過程並優化了 DNA 的保存。它被設計為一種經濟有效的生物 DNA 採集管替代品，並且在腫瘤學及其他領域具有潛在的廣泛應用。

NextCollect manufacturing and packaging is being performed by a third party. We believe that scale in NextCollect can generate gross margins in excess of 65%.

NextCollect 的製造和包裝由第三方進行。我們相信 NextCollect 的規模可以產生超過 65% 的毛利率。

With that overview, I will now turn the call over to Mark Erlander, our Chief Scientific Officer, to share details and next steps of our clinical development plans for PCM-075. Mark?

有了上述概述，我現在將把電話轉給我們的首席科學官 Mark Erlander，分享我們 PCM-075 臨床開發計劃的詳細信息和後續步驟。標記？

Thank you, Bill. Preclinical and Phase I data as well as clinical trials have been conducted with other polo-like kinase inhibitor, gives us reason to believe that PCM-075 can be a first-in-class new treatment option in AML with a straightforward clinical development plan. A Phase 1 study -- safety study has already been completed in patients with advanced solid tumor cancers with data indicating an acceptable safety profile as well as anti-tumor activity. This Phase 1 study was an open label dose escalation trial of PCM-075 given orally once daily for five consecutive days within a 21-day cycle in 19 patients. The median treatment duration was six weeks with the median number of cycles of two per patient. The results demonstrated that the on-target activity of PCM-075 indicates favorable evaluation in hematological malignancies, and no relevant off target or unexpected toxicities were observed. Additionally, the results suggest clinical activity of PCM-075 in solid tumor malignancies as a single agent or in combination therapy. A manuscript of the Phase 1 trial data is planned for submission for publication in the second quarter.

謝謝你，比爾。臨床前和 I 期數據以及其他 Polo 樣激酶抑製劑的臨床試驗使我們有理由相信 PCM-075 可以通過簡單的臨床開發計劃成為 AML 的一流新治療選擇。一期研究——針對晚期實體瘤癌症患者的安全性研究已經完成，數據顯示可接受的安全性和抗腫瘤活性。這項 1 期研究是 PCM-075 的開放標籤劑量遞增試驗，有 19 名患者在 21 天的周期內連續 5 天口服一次 PCM-075。中位治療持續時間為六週，每位患者的中位週期數為兩個。結果表明，PCM-075 的靶向活性表明在血液惡性腫瘤中具有良好的評價，並且沒有觀察到相關的脫靶或意外毒性。此外，結果表明 PCM-075 作為單一藥物或聯合治療在實體瘤惡性腫瘤中具有臨床活性。第一階段試驗數據的手稿計劃於第二季度提交出版。

As Bill said earlier, we plan to fast follow on the AML clinical development strategies performed by a large pharmaceutical company with their pan polo-like kinase inhibitor. This company's drug is an IV pan-PLK inhibitor with a half life of 135 hours. While their Phase 3 trial showed a higher number of patients responded, overall survival benefit was not statistically significant. The data showed an unfavorable overall survival trend with the safety profile and the dosing regimen considered as the primary reasons. PCM-075, as mentioned earlier, is an oral, highly selective polo-like kinase inhibitor with nanomolar affinity for PLK1 and five times shorter half life, making it potentially safer and more efficacious PLK1 inhibitor. Importantly, PLK1, the most well understood PLK family member, regulates numerous stages of mitosis and is over-expressed in many cancers, including AML. Among the five members of the PLK family, PLK1 is recognized to be the fundamental component for cell division to take place correctly, which makes PCM-075 an attractive drug candidate.

正如 Bill 之前所說，我們計劃快速跟進一家大型製藥公司的泛馬球樣激酶抑製劑實施的 AML 臨床開發策略。該公司的藥物是一種IV pan-PLK抑製劑，半衰期為135小時。雖然他們的 3 期試驗顯示有更多患者做出反應，但總體生存獲益並不具有統計學意義。數據顯示總體生存趨勢不利，安全性和給藥方案被認為是主要原因。如前所述，PCM-075 是一種口服、高選擇性 polo 樣激酶抑製劑，對 PLK1 具有納摩爾級親和力，半衰期縮短五倍，使其成為潛在更安全、更有效的 PLK1 抑製劑。重要的是，PLK1 是人們最了解的 PLK 家族成員，它調節有絲分裂的多個階段，並且在包括 AML 在內的許多癌症中過度表達。在 PLK 家族的五個成員中，PLK1 被認為是細胞分裂正確發生的基本成分，這使得 PCM-075 成為有吸引力的候選藥物。

We successfully completed the transfer of the active PCM-075 IND with the FDA from Nerviano Medical Sciences to Trovagene. Our next step is to submit an IND application to the FDA Division of Hematology products for a Phase 1/2 trial. This trial designed to determine dosing in patients with AML, provide a preliminary assessment of response and explore the use of correlative biomarker analysis to select patients most likely to respond.

我們成功完成了 FDA 將有效的 PCM-075 IND 從 Nerviano Medical Sciences 轉移到 Trovagene。我們的下一步是向 FDA 血液產品部門提交 IND 申請，進行 1/2 期試驗。該試驗旨在確定 AML 患者的劑量，提供反應的初步評估，並探索使用相關生物標誌物分析來選擇最有可能產生反應的患者。

We believe monitoring patient response with our PCM diagnostic technology will support the clinical development plans for PCM-075. Our goal is to obtain FDA acceptance of our protocol, secure trial sites and initiate our Phase 1/2 trial with the first AML patient enrolled by the end of this year. While it is still early in the PCM-075 clinical development process, we appreciate that investors would like a better understanding of the cost of our Phase 1/2 trial. Our early estimates for this trial are based on enrolling 40 to 50 patients at a cost between $8 million to $12 million for 18 months. We plan to provide improved estimates for this clinical trial as we engage the FDA and negotiate study costs with Phase 1 and 2 clinical sites.

我們相信，利用我們的 PCM 診斷技術監測患者反應將支持 PCM-075 的臨床開發計劃。我們的目標是讓 FDA 接受我們的方案，確保試驗地點安全，並在今年年底前啟動我們的 1/2 期試驗，招募第一位 AML 患者。雖然 PCM-075 臨床開發過程仍處於早期階段，但我們感謝投資者希望更好地了解我們 1/2 期試驗的成本。我們對該試驗的早期估計是招募 40 至 50 名患者，為期 18 個月，費用在 800 萬至 1200 萬美元之間。我們計劃在與 FDA 合作並與 1 期和 2 期臨床中心協商研究成本時，對該臨床試驗提供改進的估計。

We recently engaged in experienced clinical research organization or CRO to support the development of our Phase 1/2 protocol and preparation of our IND submission. We also added Dr. Sandra Silberman, a physician and leading clinical researcher, with significant experience in AML to our Clinical Advisory Board. Dr. Silverman has extensive experience in the development of novel therapies for the treatment of hematological cancers and will work with us throughout the clinical development process for PCM-075.

我們最近聘請了經驗豐富的臨床研究組織或 CRO 來支持我們 1/2 期協議的開發和 IND 提交的準備。我們還將在 AML 方面擁有豐富經驗的醫生和領先臨床研究員 Sandra Silberman 博士加入我們的臨床顧問委員會。 Silverman 博士在開發治療血液癌症的新療法方面擁有豐富的經驗，並將在整個 PCM-075 的臨床開發過程中與我們合作。

PLK inhibitors have already demonstrated clinical activity in hematological malignancies, especially in AML, with the preclinical data in support of other blood-based tumors, such as pediatric acute lymphoblastic leukemia or ALL. There is also preclinical and Phase 1 data in solid tumors, including breast, colon, ovarian, prostate, lung and bone cancers, and investigators are interested in using PCM-075 in combination therapy for the treatment of peripheral T-cell lymphoma.

PLK 抑製劑已在血液惡性腫瘤（特別是 AML）中表現出臨床活性，臨床前數據支持其他血液腫瘤（例如小兒急性淋巴細胞白血病或 ALL）。實體瘤（包括乳腺癌、結腸癌、卵巢癌、前列腺癌、肺癌和骨癌）也有臨床前和 1 期數據，研究人員有興趣使用 PCM-075 聯合療法治療外周 T 細胞淋巴瘤。

We believe PCM-075 shows great promise in AML and may have the potential to treat numerous other types of cancers. We look forward to sharing updates on our PCM-075 clinical program or our progress in the coming months.

我們相信 PCM-075 在 AML 方面顯示出巨大的前景，並可能具有治療許多其他類型癌症的潛力。我們期待在未來幾個月分享我們的 PCM-075 臨床計劃的最新信息或進展。

I will now turn the call back over to Bill. Bill?

我現在將把電話轉回給比爾。賬單？

Thank you, Mark. I'll now review briefly our financials of first quarter 2017. We reported a net loss of $10 million or $0.32 per diluted share in the first quarter of 2017 as compared to a net loss of $10.3 million or $0.36 per diluted share for the first quarter of 2016. Excluding restructuring charges of $1.7 million and a $2 million licensing fee that was expensed research and development costs from the acquisition of the Nerviano license for PCM-075, total operating expenses were approximately $6.5 million in the first quarter of 2017, a significant reduction from $10.6 million in the first quarter of 2016. We announced on March 15 a restructuring program to support the Company's expansion into precision cancer therapeutics. This restructuring is an addition to our previously announced restructuring program in December 2016. Combined, these programs reduced our annual pre-tax expenses by approximately $12 million per year, excluding one-time separation costs through the reduction of approximately 50 personnel and expenses primarily linked to research commercialization of certain diagnostic programs.

謝謝你，馬克。現在我將簡要回顧一下我們 2017 年第一季度的財務狀況。我們報告 2017 年第一季度的淨虧損為 1000 萬美元，即稀釋後每股 0.32 美元，而第一季度的淨虧損為 1030 萬美元，即稀釋後每股 0.36 美元2016 年第一季度，不包括 170 萬美元的重組費用和 200 萬美元的許可費（因購買 PCM-075 的 Nerviano 許可證而支出的研發成本），2017 年第一季度的總運營費用約為 650 萬美元，這是一個重大數字。較 2016 年第一季度的 1,060 萬美元減少。我們於 3 月 15 日宣布了一項重組計劃，以支持公司向精準癌症治療領域擴張。此次重組是我們之前於 2016 年 12 月宣布的重組計劃的補充。這些計劃合計使我們的年度稅前費用每年減少約 1200 萬美元，不包括通過減少約 50 名人員和主要相關費用而產生的一次性離職費用。研究某些診斷程序的商業化。

We have maintained our CLIA/CAP-accredited laboratory for clinical services to pharmaceutical companies and for internal activities. In total, Trovagene has approximately 25 personnel across CLIA operations, research, commercial development and general administrative services. We are working with third-party vendors, including CROs and consultants, to develop and file our Phase 1/2 study protocol with the FDA.

我們擁有 CLIA/CAP 認證的實驗室，為製藥公司提供臨床服務和內部活動。 Trovagene 總共擁有約 25 名員工，負責 CLIA 運營、研究、商業開發和一般管理服務。我們正在與第三方供應商（包括 CRO 和顧問）合作，制定並向 FDA 提交 1/2 期研究方案。

Research and development expenses for the first quarter of 2017 were $4.3 million, which included a one-time license fee of $2 million to Nerviano Medical Sciences for PCM-075. Excluding this one-time license fee, research and development expenses for the first quarter of 2017 were $2.3 million compared to $3.2 million in the first quarter of 2016, a reduction of $0.9 million.

2017年第一季度的研發費用為430萬美元，其中包括向Nerviano Medical Sciences支付的PCM-075一次性許可費200萬美元。除去這筆一次性許可費，2017年第一季度的研發費用為230萬美元，比2016年第一季度的320萬美元減少了90萬美元。

Selling and market expenses were $1.4 million in the first quarter of 2017 compared to $3.1 million for the same period in 2016, a decrease of $1.7 million as a result of reduction in sales force.

2017 年第一季度的銷售和市場費用為 140 萬美元，而 2016 年同期為 310 萬美元，由於銷售人員減少，銷售和市場費用減少了 170 萬美元。

General and administrative expenses were reduced by $1.8 million to $2.2 million in the first quarter of 2017 compared to $4 million in the first quarter of 2016, primarily due to decrease in stock-based compensation.

2017 年第一季度的一般及管理費用減少了 180 萬美元，至 220 萬美元，而 2016 年第一季度為 400 萬美元，主要是由於股票薪酬的減少。

Net cash used in operating activities in the first quarter 2017 was $8.8 million compared to $6.9 million in the first quarter of 2016. The quarter-over-quarter increase can be attributed primarily to restructuring charges and the acquisition of Nerviano license for PCM-075.

2017 年第一季度經營活動使用的現金淨額為 880 萬美元，而 2016 年第一季度為 690 萬美元。環比增長主要歸因於重組費用和收購 Nerviano 的 PCM-075 許可證。

Excluding these one-time events, net cash flow used in operating activities in the first quarter of 2017 was approximately $6.8 million. We anticipate our quarterly cash burn for the remainder of 2017 to range between $4 million to around $5 million. The weighted average of diluted shares of common stock outstanding used to calculate per share results was $31 million. As of March 31, 2017, Trovagene cash, cash equivalents and short-term investments of approximately $28.8 million.

排除這些一次性事件，2017年第一季度經營活動使用的淨現金流量約為680萬美元。我們預計 2017 年剩餘時間的季度現金消耗將在 400 萬美元至 500 萬美元左右之間。用於計算每股業績的稀釋後已發行普通股的加權平均值為 3100 萬美元。截至2017年3月31日，Trovagene的現金、現金等價物和短期投資約為2880萬美元。

We look forward to sharing our continued progress with you. Thank you for participating in today's call. And this concludes our prepared remarks. Operator, we are now ready for the question-and-answer session.

我們期待與您分享我們不斷取得的進展。感謝您參加今天的電話會議。我們準備好的發言到此結束。接線員，我們現在準備好進行問答環節了。

(Operator Instructions) Jason McCarthy, Maxim Group.

（操作員說明）Jason McCarthy，Maxim Group。

I have just two questions, one mechanistic and one clinical trial oriented. Can you describe to us or walk us through some of the differences between pan-PLK inhibitor and PCM-075? I know we've seen really good data in AML with pan-PLK inhibitors. Is there new answers of difference and I think are really important and PCM-075 could be a much better approach to AML. And on the clinical side, can you walk us through what the clinical pathway might look like, what's the size and scope of the Phase 1/2 study, and if that data is positive, could you move on to a registration study of x number of patients and maybe walk us through what you're thinking clinically? Thanks.

我只有兩個問題，一個是機械問題，一個是臨床試驗問題。您能否向我們描述或引導我們了解泛 PLK 抑製劑和 PCM-075 之間的一些差異？我知道我們已經在泛 PLK 抑製劑治療 AML 方面看到了非常好的數據。是否有新的差異答案，我認為非常重要，PCM-075 可能是一種更好的 AML 方法。在臨床方面，您能否向我們介紹一下臨床路徑可能是什麼樣子，1/2 期研究的規模和範圍是多少，如果數據是積極的，您能否繼續進行 x 數量的註冊研究患者的情況，也許可以向我們介紹一下您在臨床上的想法？謝謝。

Thanks, Jason. So Mark, why don't you handle the first question of PLK.

謝謝，傑森。那麼馬克，你為什麼不處理 PLK 的第一個問題呢？

Sure. I can start this out. Great question. Yes, there are some very distinct differences in the properties. The pan basically -- polo kinase-like inhibitor is really -- inhibits not only PLK1, but also PLK2 and PLK3. One of the reason that's important is that really only PLK1 is necessary for cell division and PLK2 and PLK3, which are inhibited by the pan inhibitor, are also present in neurons, and so they also then basically have the opportunity to cause neuropathic results as well, basically. So the issue is that this is one of the differences between the pan versus a selective. The other differences are in the actual half life. The half life of PCM-075 is about 24 hours versus 135. This is a big difference of fivefold difference. The half life of our drug PCM-075 allows you to have a lot more maneuverability with patients than that of something as such a long half-life of over 5 days. This is another fundamental difference between the two compounds. I think that (multiple speakers) the main differences.

當然。我可以開始這個。很好的問題。是的，屬性之間存在一些非常明顯的差異。基本上，Polo 激酶樣抑製劑實際上不僅抑制 PLK1，還抑制 PLK2 和 PLK3。重要的原因之一是，實際上只有 PLK1 是細胞分裂所必需的，而被泛抑製劑抑制的 PLK2 和 PLK3 也存在於神經元中，因此它們基本上也有機會引起神經病變結果， 基本上。所以問題是，這是平底鍋與選擇性之間的區別之一。其他差異在於實際半衰期。 PCM-075 的半衰期約為 24 小時，而 135 的半衰期約為 24 小時。這是五倍的巨大差異。與半衰期超過 5 天的藥物相比，我們的藥物 PCM-075 的半衰期讓您對患者有更多的可操作性。這是兩種化合物之間的另一個根本區別。我認為（多個發言者）主要區別在於。

In terms of how we think of through the studies, a lot of this -- we're working to capture the benefits of a previous pan polo kinase that was a good compound, fairly aggressive, both in terms of its makeup and in terms of even pan polo kinase as well as, as Mark mentioned, it's half life and how it's administered. So as we think through the Phase 1/2, we are actually going to get quite a bit of information as we work to get their protocol going with the FDA. One is to dose first patient AML. We've got a safety study. And in solid tumors, we're looking to get a manuscript and get that information out and show that how the drug is well tolerated in average metastatic cancer patients, but for the Phase 1/2 first dose in hematology patients, and then we'll do background chemotherapy on that for a period of various doses and then select the dose where we get longer-term, hopefully, benefit in duration. So we'll get a combination of therapeutics, tolerability and early-stage clinical efficacy in the two portion of Phase 1/2. We're also be measuring, in that study, biomarkers, both pre-imposed dose in urine and blood and others, to see about various mutations and how they either respond to the therapeutic or do not, so we compare the cells for potential of the Phase 2. And there's a lot of ways this can go. It's hard to get ahead of that until we've really had a chance to present this to the FDA, but I would hope that if we do a Phase 1 with all the data that we could approach for a Phase 2b, which would be you've got to study protocol, increase that and if it's going to drugs you want, increase the size for potential submission. That would be an aspirational hope that after this study, we do a Phase 2b, which will be potentially submittable, but that's work to be worked out. And I think this Phase 1, which will take between, as we go this year to through next year, many different data points, which we'll be getting out because it's not necessarily a blinded study, it's an active study.

就我們如何通過研究思考而言，我們正在努力捕捉以前的泛馬球激酶的好處，它是一種很好的化合物，相當具有攻擊性，無論是在其組成方面還是在甚至是泛馬球激酶，正如馬克提到的，它的半衰期以及它的給藥方式。因此，當我們思考 1/2 階段時，我們實際上會獲得相當多的信息，因為我們正在努力讓他們的協議與 FDA 合作。一種是對第一位 AML 患者進行給藥。我們進行了一項安全研究。在實體瘤中，我們希望獲得一份手稿並獲取該信息，並表明該藥物在普通轉移性癌症患者中的耐受性如何，但對於血液學患者的 1/2 期首劑，然後我們'我們將在一段時間內進行不同劑量的背景化療，然後選擇我們能夠獲得長期（希望）持續獲益的劑量。因此，我們將在 1/2 期的兩個部分中獲得治療、耐受性和早期臨床療效的結合。在這項研究中，我們還測量了生物標誌物，包括尿液和血液中預先施加的劑量以及其他生物標誌物，以了解各種突變以及它們如何對治療做出反應或不做出反應，因此我們比較了細胞的潛力第二階段。這有很多方法可以實現。在我們真正有機會將其提交給 FDA 之前，很難提前實現這一目標，但我希望，如果我們使用我們可以用於 2b 階段的所有數據進行 1 階段，那麼您就是必須研究方案，增加方案，如果是你想要的藥物，增加潛在提交的規模。在這項研究之後，我們將進行 2b 階段，這將是一個強烈的希望，該階段可能會提交，但這是有待完成的工作。我認為第一階段將在今年和明年之間進行，我們將公佈許多不同的數據點，因為這不一定是盲法研究，而是主動研究。

Okay. And then just one more follow-up to that. In the pan-PLK study, I think one of the issues, and Mark you're talking about some of the neurological off-targeting and other off-target effects, the patients were dying from lethal infections, some of the patients were prophylaxed to prevent that, somewhere not. Is that something that you're considering for your studies just as a precaution?

好的。然後還有一個後續行動。在泛 PLK 研究中，我認為問題之一，馬克，你正在談論一些神經脫靶和其他脫靶效應，患者死於致命感染，一些患者被預防防止這種情況發生，在某個地方不發生。您在學習中考慮這樣做只是為了以防萬一嗎？

Yes, absolutely. But I do think that also -- we believe that we will have a less toxic -- toxicities given that we are selective to PLK1. So that's the another reason that we feel bullish about it.

是的，一點沒錯。但我確實認為，鑑於我們對 PLK1 具有選擇性，我們相信我們的毒性會更小。這是我們看好它的另一個原因。

Ram Selvaraju, Rodman & Renshaw.

拉姆·塞爾瓦拉朱、羅德曼和倫肖。

I just wanted to ask about the kinetics of receptor binding for PCM-075. You've obviously previously commented, I believe, regarding the specific half life of the drug and how that compares to other agents that have activity against the target, but I just wanted to get a sense of the receptor binding kinetics and how that plays into the overall pharmacology of the compound, please?

我只是想問一下 PCM-075 受體結合的動力學。我相信，您之前顯然已經評論過該藥物的具體半衰期以及與其他具有針對靶點活性的藥物相比如何，但我只是想了解受體結合動力學及其如何發揮作用請問該化合物的整體藥理學嗎？

Yes, it's really -- Hi, this is Mark. It's really an inhibitor of an enzyme that's not really binding to a receptor. So it has a different -- it's a different kind of mechanism. So what we're really looking at here is PLK1 is essential for cell division, and this PLK1 inhibitor, PCM-075, has a nanomolar IC50 for that particular enzyme. That enzyme is a serine threonine kinase and so this inhibits the serine kinase activity.

是的，確實是——嗨，我是馬克。它實際上是一種酶的抑製劑，並不真正與受體結合。所以它有一個不同的——這是一種不同的機制。因此，我們在這裡真正關注的是 PLK1 對於細胞分裂至關重要，而這種 PLK1 抑製劑 PCM-075 對於該特定酶具有納摩爾 IC50。該酶是絲氨酸蘇氨酸激酶，因此它會抑製絲氨酸激酶活性。

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。您現在可以斷開連接。