Oric Pharmaceuticals Inc (ORIC) 2021 Q4 法說會逐字稿

Good day, and thank you for standing by. Welcome to the ORIC Pharmaceuticals Fourth Quarter and Full Year 2021 Financial Results and Operational Update Call. (Operator Instructions)

美好的一天，感謝您的支持。歡迎參加 ORIC Pharmaceuticals 2021 年第四季度和全年財務業績和運營更新電話會議。 （操作員說明）

Please be advised that today's conference is being recorded. (Operator Instructions) I would now like to hand the conference over to your speaker today, Dominic Piscitelli, Chief Financial Officer. Please go ahead.

請注意，今天的會議正在錄製中。 （操作員指示）我現在想將會議交給今天的發言人，首席財務官 Dominic Piscitelli。請繼續。

Good afternoon, and welcome to the ORIC Pharmaceuticals Fourth Quarter and Full Year 2021 Financial Results and Operational Update Call.

下午好，歡迎參加 ORIC Pharmaceuticals 2021 年第四季度和全年財務業績和運營更新電話會議。

Following the market close today, we filed our Form 10-K and issued a press release with our financial results for the fourth quarter and full-year ended December 31, 2021. You may find these documents posted on the Investor page of oricpharma.com.

今天收盤後，我們提交了 10-K 表格並發布了新聞稿，其中包含截至 2021 年 12 月 31 日的第四季度和全年財務業績。您可以在 oricpharma.com 的投資者頁面上找到這些文件。

We have prerecorded a portion of our prepared remarks, after which, we will host a live Q&A session. So please bear with us, if we have any technical difficulties.

我們預先錄製了部分準備好的發言，之後我們將舉辦現場問答環節。因此，如果我們遇到任何技術困難，請耐心等待。

Before we begin, starting on Slide 2, during this conference call, we will be making forward-looking statements. ORIC's actual results may differ materially from those expressed in or indicated by such forward-looking statements.

在我們開始之前，從幻燈片 2 開始，在本次電話會議期間，我們將做出前瞻性聲明。 ORIC 的實際結果可能與此類前瞻性陳述中表達或表明的結果存在重大差異。

For a description of risk factors associated with investing in ORIC, please refer to our recent filings with the Securities and Exchange Commission. ORIC specifically disclaims any obligation to update any forward-looking statements, except as required by law.

有關投資 ORIC 相關風險因素的說明，請參閱我們最近向美國證券交易委員會提交的文件。除法律要求外，ORIC 特別不承擔更新任何前瞻性陳述的義務。

Now, turning to Slide 3. I'll briefly walk you through our agenda and introduce our speakers. During today's call, we're primarily focused on an update on ORIC-101, after which we'll provide a pipeline update and summary, followed by Q&A.

現在，轉向幻燈片 3。我將簡要介紹我們的議程並介紹我們的發言人。在今天的電話會議中，我們主要關注 ORIC-101 的更新，之後我們將提供管道更新和摘要，然後是問答。

Joining me on the call today we have Jacob Chacko, CEO; and Pratik Multani, CMO. Now, let me turn over the call to Jacob.

今天與我一起參加電話會議的是首席執行官 Jacob Chacko；和首席營銷官 Pratik Multani。現在，讓我把電話轉給雅各布。

Thank you, Dominic. Turning to Slide 4. As you know, over the past 2-plus years, we have conducted dose escalation and dose expansion studies, testing 2 separate therapeutic hypotheses for GR inhibition as a means of overcoming resistance to chemotherapy in various solid tumors and to AR modulators in prostate cancer.

謝謝你，多米尼克。轉向幻燈片 4。如您所知，在過去兩年多的時間裡，我們進行了劑量遞增和劑量擴展研究，測試了 GR 抑制的 2 個單獨的治療假設，作為克服各種實體瘤對化療和 AR 耐藥的方法前列腺癌的調節劑。

We recently completed interim analyses from both combination studies, and we believe that further development of ORIC-101 should be discontinued due to a lack of sufficient efficacy signal to meet our benchmarks, which Pratik will tell you more about shortly.

我們最近完成了兩項組合研究的中期分析，我們認為，由於缺乏足夠的療效信號來滿足我們的基準，我們認為應該停止 ORIC-101 的進一步開發，Pratik 將很快告訴您更多相關信息。

In both studies, we took on a difficult challenge, namely, in later-line patients, who had already progressed on a prior cancer therapeutic. We were attempting to add a GR antagonist, in order to resensitize them to that prior therapeutic.

在這兩項研究中，我們都面臨著一項艱鉅的挑戰，即針對在先前的癌症治療中已經取得進展的後期患者。我們試圖添加 GR 拮抗劑，以使他們對之前的治療重新敏感。

While that was a high bar, it was an important clinical question to evaluate because of the limited treatment options available to those patients today. The challenges of assessing efficacy signal in a single-arm study of a combination regimen are obvious.

雖然這是一個很高的標準，但由於當今這些患者可用的治療選擇有限，因此這是一個需要評估的重要臨床問題。在聯合治療方案的單臂研究中評估療效信號的挑戰是顯而易見的。

So our team put in place 2 well-designed clinical trials that were complemented by a robust translational effort. We're confident that we've explored the GR hypothesis appropriately and also confident in making this decision.

因此，我們的團隊開展了兩項精心設計的臨床試驗，並輔以強有力的轉化工作。我們有信心我們已經正確地探索了 GR 假設，也有信心做出這個決定。

While we're obviously disappointed that ORIC-101 is not continuing, we're proud of the scientific rigor and thoughtful clinical design that allowed us to make an efficient but thorough decision. Despite the discontinuation of ORIC-101, we believe we have one of the most robust and differentiated pipelines in small-cap biotech.

雖然我們顯然對 ORIC-101 沒有繼續進行感到失望，但我們為科學嚴謹和深思熟慮的臨床設計感到自豪，這使我們能夠做出高效而徹底的決定。儘管 ORIC-101 已停產，但我們相信我們擁有小型生物技術領域最強大和最差異化的產品線之一。

We've been intentional about assembling a broader pipeline of both novel and validated targets that are attempting to address areas of high unmet need with either first-in-class or potentially best-in-class approaches.

我們一直有意整合更廣泛的新穎和經過驗證的目標管道，試圖通過一流或潛在一流的方法來解決高度未滿足需求的領域。

Last year, we filed 3 INDs or equivalents for single-agent trials being initiated this year for ORIC-533 in multiple myeloma, ORIC-114 in EGFR/HER2 cancers and ORIC-944 in prostate cancer, with data from all 3 programs expected in the first half of 2023. Each of these programs has a unique angle or angles that we believe will help differentiate them in the clinic.

去年，我們為今年啟動的針對多發性骨髓瘤的 ORIC-533、針對 EGFR/HER2 癌症的 ORIC-114 和針對前列腺癌的 ORIC-944 的單藥試驗提交了 3 個 IND 或等效文件，預計所有 3 個項目的數據將於2023 年上半年。每個項目都有一個或多個獨特的角度，我們相信這將有助於它們在臨床中脫穎而出。

Beyond these 3 clinical-stage programs, our discovery research team, last year, advanced 2 programs into lead optimization, one of which we recently introduced as our PLK4 program, which we believe is a first-in-class synthetic-lethality approach for breast cancer.

除了這 3 個臨床階段項目之外，我們的發現研究團隊去年還推進了 2 個先導化合物優化項目，其中一個項目是我們最近推出的 PLK4 項目，我們相信這是一種一流的乳腺合成致死方法癌症。

Finally, we've been thoughtful about bolstering our balance sheet and managing our resources efficiently, so we believe we're well capitalized to weather a sustained market downturn.

最後，我們一直在考慮加強我們的資產負債表和有效管理我們的資源，因此我們相信我們有充足的資本來應對持續的市場低迷。

With the discontinuation of ORIC-101, our cash runway has now been extended from the first half of 2024 to the second half of 2024. And that guidance assumes advancement of all our pipeline programs.

隨著 ORIC-101 的終止，我們的現金跑道現已從 2024 年上半年延長至 2024 年下半年。該指導假設我們所有管道項目都取得進展。

With that said, let me now turn the call over to Pratik to walk you through the summary highlights of the ORIC-101 studies.

話雖如此，現在讓我將電話轉給 Pratik，帶您了解 ORIC-101 研究的摘要要點。

Thank you, Jacob. Turning to Slide 6. We have been conducting 2 clinical trials of ORIC-101, each examining a distinct mechanism of action of GR inhibition as a means to reverse cancer resistance.

謝謝你，雅各布。轉向幻燈片 6。我們一直在進行 2 項 ORIC-101 臨床試驗，每項試驗都檢查 GR 抑制的獨特作用機制，作為逆轉癌症耐藥性的一種手段。

The first study is a combination of ORIC-101 with enzalutamide in patients with metastatic prostate cancer. Given that ORIC-101 was not expected to have single-agent activity, we chose this patient population specifically so that we could identify a clinical signal in a single-arm setting as efficiently as possible, namely patients with metastatic prostate cancer, who are progressing on enzalutamide.

第一項研究是 ORIC-101 與恩雜魯胺聯合治療轉移性前列腺癌患者。鑑於 ORIC-101 預計不會具有單藥活性，我們專門選擇了這一患者群體，以便我們能夠在單臂環境中盡可能有效地識別臨床信號，即正在進展的轉移性前列腺癌患者恩雜魯胺。

By adding ORIC-101 at the time of enzalutamide progression, our objective was to test the hypothesis of reversal of enzalutamide resistance through the simultaneous inhibition of GR as a potential bypass pathway, a novel paradigm for treatment post-enzalutamide or any androgen receptor modulator, since most second-line approaches involve switching to entirely different mechanisms of action. Here, we were trying to extend the efficacy of enzalutamide itself.

通過在恩雜魯胺進展時添加 ORIC-101，我們的目的是測試通過同時抑制 GR 作為潛在旁路途徑逆轉恩雜魯胺耐藥性的假設，這是恩雜魯胺或任何雄激素受體調節劑後治療的新範例，因為大多數二線方法涉及轉向完全不同的作用機制。在這裡，我們試圖擴展恩雜魯胺本身的功效。

This multicenter, open-label study was performed in 2 parts. We previously reported on Part 1, which was the dose escalation portion of the trial, through which we identified the recommended Phase II dose, or RP2D, of ORIC-101 to be 240 milligrams, once daily, in combination with standard dose enzalutamide.

這項多中心、開放標籤研究分兩部分進行。我們之前報導了第 1 部分，即試驗的劑量遞增部分，通過該部分，我們確定了 ORIC-101 的推薦 II 期劑量（RP2D）為 240 毫克，每日一次，與標準劑量恩雜魯胺聯合使用。

The determination of ORIC-101 dose relied heavily on extensive translational work that was an integral component of the trial. This effort included baseline and on-study tumor biopsies and serial blood sampling for pharmacokinetics -- pharmacodynamics of GR signaling and tumor genomic profiling at baseline and longitudinally on study.

ORIC-101劑量的確定在很大程度上依賴於廣泛的轉化工作，這是該試驗的一個組成部分。這項工作包括基線和研究中的腫瘤活檢以及用於藥代動力學的連續血液採樣——GR信號傳導的藥效學以及基線和縱向研究的腫瘤基因組分析。

Pharmacokinetic sampling demonstrated that at the RP2D, we were achieving exposures of ORIC-101 that were sufficient to inhibit the target. And through our pharmacodynamic studies, we were also able to confirm that we were achieving target shutdown through the measurement of downstream GR target genes.

藥代動力學採樣表明，在 RP2D 中，我們獲得了足以抑制靶標的 ORIC-101 暴露量。通過我們的藥效學研究，我們還能夠通過測量下游 GR 靶基因來確認我們正在實現目標關閉。

After establishing the RP2D, we enrolled patients into the dose expansion portion of the trial with a planned interim analysis after 28 patients. The primary endpoint of Part 2 was disease control rate at 12 weeks, with progression-free survival as an important secondary endpoint.

建立 RP2D 後，我們將患者納入試驗的劑量擴展部分，併計劃對 28 名患者進行中期分析。第 2 部分的主要終點是 12 週時的疾病控制率，無進展生存期是重要的次要終點。

Another important consideration was that through the profiling of patient tumors at baseline, we were able to identify a target patient population for ORIC-101, in which we would expect GR to be a potentially active mechanism of resistance.

另一個重要的考慮因素是，通過基線時患者腫瘤的分析，我們能夠確定 ORIC-101 的目標患者群體，我們預計 GR 是一種潛在的活躍耐藥機制。

This population excludes patients whose tumors harbor one of the well-described alternate mechanisms of resistance, namely primary resistance variance of the androgen receptor, such as splice variance or point mutations that inhibit enzalutamide binding in markers of lineage plasticity, implying that the cancer had become AR independent.

該人群排除了腫瘤具有已知的替代耐藥機制之一的患者，即雄激素受體的原發性耐藥變異，例如抑制恩雜魯胺在譜係可塑性標誌物中結合的剪接變異或點突變，這意味著癌症已成為AR 獨立。

In addition, we would also focus on the patients whose tumors were high expressers of the glucocorticoid receptor, which is the target of ORIC-101. After enrolling 10 patients to identify the RP2D in Part 1, per protocol, we enrolled 28 patients into the dose expansion and followed them for at least 12 weeks, in order to perform the primary efficacy analysis of disease control rate.

此外，我們還將重點關注腫瘤高表達糖皮質激素受體的患者，而糖皮質激素受體是 ORIC-101 的靶點。在第 1 部分中招募 10 名患者來識別 RP2D 後，根據方案，我們招募了 28 名患者進行劑量擴展，並對他們進行至少 12 週的隨訪，以進行疾病控制率的主要療效分析。

Whereas previously, with small numbers, we had focused on time on treatment as an outcome measure, now, with the additional patients and follow-up, we shifted to our secondary endpoint of progression-free survival, which has ample regulatory precedent.

以前，在人數較少的情況下，我們將治療時間作為結果衡量指標，而現在，隨著患者數量的增加和隨訪，我們轉向了無進展生存期的次要終點，這有充足的監管先例。

And although this was a single-arm study, we referenced as benchmarks of efficacy, the progression-free survival for such agents as cabazitaxel and docetaxel, which are used in the post-enzalutamide setting, as well as the new agents and combinations that are in development, such as cabozantinib plus atezolizumab.

儘管這是一項單臂研究，但我們參考了卡巴他賽和多西他賽等藥物的無進展生存期作為療效基準，這些藥物用於恩雜魯胺治療後，以及新藥物和組合正在開發中，例如卡博替尼加阿特珠單抗。

Turning to Slide 7. Let me summarize the results of this analysis. First, in terms of safety, the combination regimen was generally well-tolerated at the recommended Phase II dose.

轉向幻燈片 7。讓我總結一下此分析的結果。首先，就安全性而言，在推薦的 II 期劑量下，聯合方案通常具有良好的耐受性。

Next, with respect to drug exposure and target engagement, extensive PK/PD work demonstrated that we were achieving ORIC-101 levels sufficient for GR target coverage, which we were able to confirm by measuring the down regulation of GR target genes.

接下來，關於藥物暴露和靶點參與，廣泛的 PK/PD 工作表明，我們達到了足以覆蓋 GR 靶點的 ORIC-101 水平，我們能夠通過測量 GR 靶點基因的下調來證實這一點。

Finally, based upon tumor biopsies at baseline, we identified that the majority of patient tumors expressed moderate to high levels of GR.

最後，根據基線時的腫瘤活檢，我們發現大多數患者腫瘤表達中等到高水平的 GR。

Nevertheless, despite achieving ORIC-101 exposures consistent with biological activity, we were not able to demonstrate evidence of sufficient clinical benefit on any of the efficacy endpoints.

然而，儘管 ORIC-101 暴露量與生物活性一致，但我們無法證明任何療效終點有足夠的臨床益處。

In particular, the primary endpoint of disease control rate at 12 weeks in the target patient population of patients with moderate-to-high GR expression and no evidence of alternate resistance through AR alterations or lineage plasticity was 33.3%, and the median PFS in the same patient population was 3.7 months.

特別是，在GR中度至高表達且沒有證據表明通過AR改變或譜係可塑性產生替代耐藥的目標患者群體中，12週時疾病控制率的主要終點為33.3%，中位PFS為33.3%。相同的患者群體為 3.7 個月。

Of note, these values were not meaningfully different from the DCR and PFS recorded in the unselected patient population.

值得注意的是，這些值與未選擇的患者群體中記錄的 DCR 和 PFS 沒有顯著差異。

In the context of the efficacy of approved therapies for patients after progression on an AR modulator, as well as the efficacy data with new therapies and regimens currently in development, the outcomes seen in our study of ORIC-101 with enzalutamide were insufficient to support continued development.

鑑於批准的療法對 AR 調節劑進展後患者的療效，以及目前正在開發的新療法和方案的療效數據，我們在 ORIC-101 聯合恩雜魯胺的研究中看到的結果不足以支持繼續發展。

Turning to Slide 9. The second trial studied ORIC-101 in combination with nab-paclitaxel in patients with advanced solid tumors. This multicenter, open-label study was also performed in 2 parts.

轉向幻燈片 9。第二項試驗研究了 ORIC-101 聯合白蛋白結合型紫杉醇治療晚期實體瘤患者。這項多中心、開放標籤研究也分兩部分進行。

We previously reported on Part 1, which was the dose escalation portion of the trial, through which we identified the RP2D of ORIC-101 in combination with nab-paclitaxel to be 160 milligrams of ORIC-101, with 75 milligrams per meter squared of nab-paclitaxel, weekly, for 3 weeks on a 4-week cycle.

我們之前報導過第 1 部分，即試驗的劑量遞增部分，通過該部分，我們確定了 ORIC-101 與白蛋白結合型紫杉醇聯合用藥的 RP2D 為 160 毫克 ORIC-101，其中每平方米白蛋白結合型紫杉醇 75 毫克- 紫杉醇，每週一次，每 4 週為一個週期，持續 3 週。

In this study, as with the enzalutamide study, we had an extensive translational component, including pharmacokinetic sampling and pharmacodynamic testing of GR target genes, which demonstrated that at the RP2D, we were achieving exposures of ORIC-101 sufficient to inhibit the target and that we were achieving target shutdown.

在這項研究中，與恩雜魯胺研究一樣，我們有廣泛的轉化部分，包括 GR 靶基因的藥代動力學採樣和藥效學測試，這證明在 RP2D 時，我們實現了足以抑制靶標的 ORIC-101 暴露，並且我們正在實現關閉目標。

In the nab-paclitaxel dose, although lower than the label dose for frontline therapy, resulted in rates of neutropenia without growth factor support that indicated that we had a sufficient dose for these late-line patients.

在白蛋白結合型紫杉醇劑量中，雖然低於一線治療的標籤劑量，但在沒有生長因子支持的情況下導致中性粒細胞減少症發生率，這表明我們為這些晚期患者提供了足夠的劑量。

After establishing the RP2D, we enrolled patients in the multi-cohort dose expansion portion of the trial with 3 cohorts of interest: pancreatic ductal adenocarcinoma, ovarian cancer and triple-negative breast cancer. And the fourth cohort opened to patients with other tumor types.

建立 RP2D 後，我們將患者納入試驗的多隊列劑量擴展部分，其中包括 3 個感興趣的隊列：胰腺導管腺癌、卵巢癌和三陰性乳腺癌。第四組向其他腫瘤類型的患者開放。

The primary endpoint of Part 2 was objective response rate, with progression-free survival as an important secondary endpoint.

第 2 部分的主要終點是客觀緩解率，無進展生存期是重要的次要終點。

The eligible patient population was defined to, again, put us in the best position to identify clinical signal in a single-arm setting as efficiently as possible. Specifically, we required patients in the dose expansion to have previously been treated with and progressed on a taxane-based therapy.

合格的患者群體的定義再次使我們處於盡可能有效地識別單臂環境中的臨床信號的最佳位置。具體來說，我們要求劑量擴大的患者之前接受過基於紫杉烷的治療並取得進展。

While this is a higher bar, we felt that only in this way, could we distinguish an ORIC-101 effect from pure taxane-driven clinical activity. While there is a taxane retreatment effect in ovarian cancer and TNBC, this effect is generally modest, and so we set a benchmark for PFS in our study, of 6 months, for ovarian cancer.

雖然這是一個更高的標準，但我們認為只有這樣，我們才能將 ORIC-101 效應與純紫杉烷驅動的臨床活動區分開來。雖然紫杉烷類藥物對卵巢癌和 TNBC 具有再治療作用，但這種作用通常不大，因此我們在研究中為卵巢癌設定了 6 個月的 PFS 基準。

On the other hand, in relapsed PDAC, there is no measurable taxane retreatment effect reported in the literature, and so we were looking to achieve a PFS of 3 months or longer with ORIC-101 and nab-paclitaxel in this cohort.

另一方面，對於復發性 PDAC，文獻中沒有報導可測量的紫杉烷再治療效果，因此我們希望在該隊列中使用 ORIC-101 和白蛋白結合型紫杉醇實現 3 個月或更長時間的 PFS。

After enrolling 21 patients to identify the RP2D in Part 1, we enrolled a total of 61 patients across the 4 dose expansion cohorts and followed them for at least 12 weeks, in order to perform the primary efficacy analysis.

在第 1 部分中招募了 21 名患者來識別 RP2D 後，我們在 4 個劑量擴展隊列中總共招募了 61 名患者，並對他們進行至少 12 週的隨訪，以進行主要療效分析。

Turning to Slide 10. The safety profile of this combination regimen was generally well tolerated at the recommended Phase II dose. And as I stated, PK data showed good target coverage, and PD data demonstrated evidence of target engagement.

轉向幻燈片 10。在推薦的 II 期劑量下，這種聯合方案的安全性通常具有良好的耐受性。正如我所說，PK 數據顯示了良好的目標覆蓋率，PD 數據顯示了目標參與的證據。

In addition, baseline biopsy of patient tumors showed high levels of GR expression across most tumor types, but particularly in 2 of the tumor types of interest: PDAC and ovarian cancer.

此外，患者腫瘤的基線活檢顯示大多數腫瘤類型都有高水平的 GR 表達，特別是在 2 種感興趣的腫瘤類型中：PDAC 和卵巢癌。

Expression was so high across most patients tested in these 2 tumor types that preselection by GR status was not necessary to identify subset target patient population.

在這 2 種腫瘤類型中測試的大多數患者中表達如此之高，因此不需要通過 GR 狀態進行預選來識別目標患者群體子集。

Although we demonstrated evidence of biological activity and high levels of the target glucocorticoid receptor, we saw only 1 confirmed partial response in the ovarian cancer cohort and no objective responses in the PDAC cohort. Furthermore, the median progression-free survivals were 1.9 months at PDAC and 2.2 months in ovarian cancer.

儘管我們證明了生物活性和高水平目標糖皮質激素受體的證據，但我們在卵巢癌隊列中僅看到 1 例經證實的部分緩解，而在 PDAC 隊列中沒有客觀緩解。此外，PDAC 的中位無進展生存期為 1.9 個月，卵巢癌的中位無進展生存期為 2.2 個月。

In these patients, who were taxane pretreated, we did not see sufficient evidence that the addition of ORIC-101 to nab-paclitaxel-reversed resistance and resensitized these patients' tumors to retreatment with taxane chemotherapy.

在這些接受紫杉烷預處理的患者中，我們沒有看到足夠的證據表明，在白蛋白結合型紫杉醇中添加 ORIC-101 可逆轉耐藥性並使這些患者的腫瘤對紫杉烷化療再治療重新敏感。

Therefore, we conclude from these data -- in these expansion cohorts, that there was insufficient activity to support continued clinical development of this regimen.

因此，我們從這些數據中得出結論——在這些擴展隊列中，沒有足夠的活動來支持該方案的持續臨床開發。

Now, turning to Slide 11. I'd like to review what we've learned from these 2 clinical trials and consider how that might help us interpret the clinical data presented here today and offer our opinion on why we may not have seen sufficient clinical benefit.

現在，轉向幻燈片 11。我想回顧一下我們從這兩項臨床試驗中學到的知識，並考慮這如何幫助我們解釋今天提供的臨床數據，並就為什麼我們可能沒有看到足夠的臨床數據提供我們的意見。益處。

First, we learned that a glucocorticoid receptor inhibitor could be safely combined with both cytotoxic chemotherapy as well as an androgen receptor modulator.

首先，我們了解到糖皮質激素受體抑製劑可以安全地與細胞毒性化療以及雄激素受體調節劑聯合使用。

Second, we learned that in these combinations, ORIC-101 was capable of achieving clinical exposures in patients, sufficient to cover and inhibit the target glucocorticoid receptor. We could measure this effect of GR target shutdown in patient samples, longitudinally, over the course of treatment.

其次，我們了解到，在這些組合中，ORIC-101能夠在患者中實現臨床暴露，足以覆蓋和抑制目標糖皮質激素受體。我們可以在治療過程中縱向測量患者樣本中 GR 靶點關閉的影響。

So if we were hitting and shutting down the target, then why did we not see clinical effect? From the translational work we performed as part of both studies, the tumor genomic profiling suggested that an answer may lie in tumor heterogeneity and/or redundancy of resistance mechanisms.

那麼，如果我們達到並關閉了目標，那麼為什麼我們沒有看到臨床效果呢？從我們作為這兩項研究的一部分進行的轉化工作來看，腫瘤基因組分析表明，答案可能在於腫瘤異質性和/或耐藥機制的冗餘。

By tumor heterogeneity, I mean differences within tumor lesions and between tumor lesions in the relevance of GR as a resistance pathway. In a single tumor, some cells may indeed be reliant upon GR as a resistance pathway, but other cells in that same tumor may be relying upon alternate non-GR mechanisms.

我所說的腫瘤異質性是指腫瘤病灶內以及腫瘤病灶之間 GR 作為耐藥途徑的相關性的差異。在單個腫瘤中，某些細胞可能確實依賴 GR 作為耐藥途徑，但同一腫瘤中的其他細胞可能依賴於替代的非 GR 機制。

A similar difference could also be present between 2 separate tumors within a single patient. We would expect that ORIC-101 would only affect the cells with GR as a resistance mechanism while not affecting the other cells, resulting in absence of measurable clinical benefit.

同一患者體內的兩個不同腫瘤之間也可能存在類似的差異。我們預計 ORIC-101 只會影響以 GR 作為耐藥機制的細胞，而不會影響其他細胞，從而導致缺乏可測量的臨床益處。

In addition, resistance pathways may be redundant within a cell. In such a setting, one or more coexisting resistance pathways, in addition to GR, may be sufficient to drive tumor progression, when GR is inhibited. Such tumor complexity may be a possible explanation for the lack of clinical benefit seen in these 2 clinical trials.

此外，細胞內的耐藥途徑可能是多餘的。在這種情況下，當 GR 被抑制時，除了 GR 之外，一種或多種共存的耐藥途徑可能足以驅動腫瘤進展。這種腫瘤的複雜性可能是這兩項臨床試驗中缺乏臨床益處的可能解釋。

And then finally, it's possible that the GR pathway itself is not a key tumor dependency in patients. And so observations made in the lab don't transfer to patients in a clinical setting.

最後，GR 通路本身可能並不是患者的關鍵腫瘤依賴性。因此，實驗室中的觀察結果不會轉移到臨床環境中的患者身上。

We're obviously disappointed that the results from these 2 clinical trials didn't meet our bar for clinical benefit and further development. Negative trials are not uncommon in oncology drug development, especially when studying novel target biology, which doesn't always translate into the clinic.

我們顯然對這兩項臨床試驗的結果沒有達到我們的臨床效益和進一步開發的標準感到失望。陰性試驗在腫瘤藥物開發中並不罕見，特別是在研究新的靶標生物學時，這並不總是能轉化為臨床。

For that reason, we designed these studies with clearly defined patient populations to enable us to get to an answer as quickly and as efficiently as possible. I think we achieved that.

出於這個原因，我們設計了這些具有明確定義的患者群體的研究，以使我們能夠盡可能快速、有效地得到答案。我認為我們做到了。

The studies were well run and they delivered sufficient data to enable us to make the tough but right decision to discontinue the ORIC-101 program. We expect to share more details on these clinical studies in future publications.

這些研究進展順利，提供了足夠的數據，使我們能夠做出終止 ORIC-101 計劃的艱難但正確的決定。我們希望在未來的出版物中分享有關這些臨床研究的更多細節。

In conclusion, I would like to thank the ORIC-101 team, the study investigators and the study support staff at all our participating clinical sites, and most of all, the patients who participated in the trials and their families.

最後，我要感謝 ORIC-101 團隊、所有參與臨床中心的研究研究者和研究支持人員，最重要的是參與試驗的患者及其家人。

With that, let me hand it back to Jacob.

就這樣，讓我把它交還給雅各布。

Thank you, Pratik. Now, turning to Slide 13. At ORIC, our mission is overcoming resistance in cancer, an inherently challenging goal. It's for that reason that we have adhered to certain core principles to guide our journey.

謝謝你，普拉蒂克。現在，轉向幻燈片 13。在 ORIC，我們的使命是克服癌症的耐藥性，這是一個本質上具有挑戰性的目標。正是出於這個原因，我們堅持某些核心原則來指導我們的旅程。

First, our patients are battling for their lives, so we're going to continue tackling areas of high unmet need, where we can have a meaningful impact.

首先，我們的患者正在為自己的生命而戰，因此我們將繼續解決需求未得到滿足的領域，我們可以在這些領域產生有意義的影響。

Second, we will continue to design trials that allow us to make data-driven decisions and get to an answer as efficiently as possible, so we can allocate resources into our most-promising programs.

其次，我們將繼續設計試驗，使我們能夠做出數據驅動的決策並儘可能有效地獲得答案，以便我們可以將資源分配到最有前途的項目中。

And finally, we've been explicit about our intent to assemble a pipeline through both internal discovery and external BD that has a mixture of novel first-in-class targets that rely on differentiated biological insights, as well as potentially best-in-class chemistry approaches to validated targets, in order to strike the right aggregate risk profile across the entire pipeline.

最後，我們明確表示我們打算通過內部發現和外部 BD 建立一條管道，該管道混合了依賴於差異化生物學見解的新穎的一流目標，以及潛在的一流目標化學方法來驗證目標，以便在整個管道中達到正確的總體風險狀況。

Last year, we filed 3 INDs or equivalents for single-agent trials being initiated this year, for ORIC-533 in multiple myeloma, ORIC-114 in EGFR/HER2 cancers and ORIC-944 in prostate cancer, with data from all 3 programs expected in the first half of 2023.

去年，我們為今年啟動的單藥試驗提交了 3 份 IND 或等效文件，其中包括治療多發性骨髓瘤的 ORIC-533、治療 EGFR/HER2 癌症的 ORIC-114 和治療前列腺癌的 ORIC-944，預計所有 3 個項目的數據均已獲得2023年上半年。

In just the first quarter of this year, we've enrolled our first patient on ORIC-533, we've cleared our CTA and initiated multiple clinical sites in Korea for ORIC-114, and we're in the process of activating sites for ORIC-944.

僅在今年第一季度，我們就在 ORIC-533 上招募了第一位患者，我們已經通過了 CTA 並在韓國啟動了 ORIC-114 的多個臨床中心，並且我們正在激活 ORIC-114 的中心。 ORIC-944。

Beyond these 3 clinical stage programs, our discovery research team, last year, advanced 2 programs in the lead optimization, one of which we recently introduced as our PLK4 program, focused on novel, highly selective inhibitors, targeting a synthetic-lethality approach as a potential treatment for breast cancer.

除了這 3 個臨床階段項目之外，我們的發現研究團隊去年在先導化合物優化方面推進了 2 個項目，其中一個是我們最近推出的 PLK4 項目，專注於新型、高選擇性抑製劑，以合成致死方法為目標乳腺癌的潛在治療方法。

In short, although 101 is not progressing to the next stage, our pipeline is one of the most robust in small-cap biotech, and we remain committed to our goal of developing life-changing therapies for patients with cancer.

簡而言之，儘管 101 尚未進入下一階段，但我們的產品線是小型生物技術領域最強大的產品線之一，我們仍然致力於為癌症患者開發改變生活的療法的目標。

Now, let me turn it over to Dominic to summarize our financials, revised cash runway and upcoming milestones.

現在，讓我把它交給多米尼克來總結我們的財務狀況、修訂後的現金跑道和即將到來的里程碑。

Thanks, Jacob. Turning to Slide 14. Operating expenses for the fourth quarter of 2021 totaled $22.8 million, resulting in a net loss of $22.8 million. For the full-year 2021, operating expenses totaled $78.9 million, resulting in a net loss of $78.7 million.

謝謝，雅各布。轉向幻燈片 14。2021 年第四季度的運營費用總計 2280 萬美元，導致淨虧損 2280 萬美元。 2021 年全年運營費用總計 7890 萬美元，淨虧損 7870 萬美元。

Net cash used in operating activities for the 12 months ended December 31, 2021 totaled approximately $60 million. We ended the year with $280.4 million in cash and investments.

截至 2021 年 12 月 31 日的 12 個月經營活動使用的現金淨額總計約為 6000 萬美元。年底，我們擁有 2.804 億美元的現金和投資。

As a result of the discontinuation of ORIC-101, we now expect our cash runway to extend into the second half of 2024, which is well beyond the expected initial data disclosures from our 3 clinical programs in the first half of 2023.

由於 ORIC-101 的停產，我們現在預計我們的現金跑道將延長至 2024 年下半年，這遠遠超出了 2023 年上半年我們 3 個臨床項目的初始數據披露預期。

Please see our press release and 10-K for additional details about our fourth quarter and full-year 2021 financial results.

請參閱我們的新聞稿和 10-K，了解有關我們第四季度和 2021 年全年財務業績的更多詳細信息。

We'll wrap up our prepared remarks on Slide 15. We're very proud of the team and pipeline that we've assembled here at ORIC. While we are disappointed that ORIC-101 won't be advancing, we've always been committed to making rapid and data-driven decisions, and we are excited about the robust pipeline of potential best-in-class and first-in-class molecules that we have assembled.

我們將在幻燈片 15 上結束我們準備好的發言。我們對在 ORIC 組建的團隊和管道感到非常自豪。雖然我們對 ORIC-101 不會取得進展感到失望，但我們始終致力於做出快速且數據驅動的決策，並且我們對潛在的一流和一流的強大管道感到興奮我們組裝的分子。

We expect to provide data updates from our 3 ongoing clinical programs in the first half of 2023. These include initial Phase I data from ORIC-533 in patients with multiple myeloma, initial Phase I data from ORIC-114 in EGFR/HER2-driven cancers and initial Phase I data from ORIC-944 in patients with prostate cancer.

我們預計在 2023 年上半年提供 3 個正在進行的臨床項目的數據更新。其中包括 ORIC-533 在多發性骨髓瘤患者中的初始 I 期數據、ORIC-114 在 EGFR/HER2 驅動的癌症中的初始 I 期數據以及來自 ORIC-944 在前列腺癌患者中的初始 I 期數據。

Before we open it up to Q&A, I'd like to thank all the investigators and the entire ORIC team, who've worked throughout the COVID pandemic to continue tackling our mission on behalf of patients.

在我們進行問答之前，我要感謝所有研究人員和整個 ORIC 團隊，他們在整個新冠病毒大流行期間一直致力於代表患者繼續完成我們的使命。

And most importantly, I'd like to thank our patients and their families, whom we hope to help overcome resistance in cancer.

最重要的是，我要感謝我們的患者及其家人，我們希望幫助他們克服癌症耐藥性。

With that, let's open it up to Q&A.

接下來，讓我們開始問答。

(Operator Instructions) Our first question will come from the line of Anupam Rama from JPMorgan.

（操作員說明）我們的第一個問題將來自摩根大通的 Anupam Rama。

I know, on Slide 11, you guys outlined the potential reasons for a lack of benefit with ORIC-101. But I guess, more mechanistically, like where do you think the thesis broke down here, given Corcept had [stat sig] results in ovarian cancer, and you guys showed some interesting, sort of, stable disease duration benefits in PDAC, previously?

我知道，在幻燈片 11 上，你們概述了 ORIC-101 缺乏益處的潛在原因。但我想，從更機械的角度來說，考慮到 Corcept 在卵巢癌方面有 [stat sig] 結果，並且你們之前在 PDAC 中表現出了一些有趣的、某種穩定的疾病持續時間的益處，那麼您認為這篇論文在哪裡失敗了？

Anupam, I'll have Pratik take that.

Anupam，我會讓 Pratik 拿走。

Anupam, it's a good question. I think it's a little bit hard for us to comment on the Corcept data, especially in the ovarian cancer study, because we don't have full insight into their study beyond some of the top-line results in their conference presentation from last year.

阿努潘，這是個好問題。我認為我們對 Corcept 的數據進行評論有點困難，尤其是在卵巢癌研究中，因為除了去年會議演講中的一些重要結果之外，我們對他們的研究沒有全面的了解。

But I do think that 2 populations, theirs and ours, are likely different and were treated differently. Our study is, we've emphasized required patients to have received and progressed on a taxane-containing regimen. And we don't know how that compares with the relacorilant study, as they require platinum-resistance, but were silent on taxane progression.

但我確實認為，他們的和我們的這兩個群體可能是不同的，並且受到的待遇也不同。我們的研究強調，要求患者接受含紫杉烷的治療方案並取得進展。我們不知道這與相關研究相比如何，因為它們需要鉑抗性，但對紫杉烷進展保持沉默。

Also, if you look at their presentation from last year, their population had 2.5 prior therapies in the ovarian cancer study, whereas ours, it's 4 prior therapies. So certainly, we had a more refractory population.

另外，如果你看一下他們去年的演示，就會發現他們的人群在卵巢癌研究中接受過 2.5 種先前療法，而我們的人群則有 4 種先前療法。所以可以肯定的是，我們的人口更加難控制。

And by design, we wanted patients who are taxane-refractory because we wanted to demonstrate an ORIC-101 effect and not a taxane retreatment effect, which can be seen in ovarian cancer.

按照設計，我們想要對紫杉烷難治的患者進行治療，因為我們想要證明 ORIC-101 的效果，而不是紫杉烷再治療的效果，後者可以在卵巢癌中看到。

We don't have the taxane interaction with ORIC-101, the PK interaction, but the relacorilant molecule does. And we don't know the PK across the 3 arms of their study.

我們沒有與 ORIC-101 之間的紫杉烷相互作用，即 PK 相互作用，但 relacorilant 分子卻有。我們不知道他們研究的 3 個分支之間的 PK。

And then finally, we've also worked hard to develop a regimen that did not require growth-factor support, prophylactically, which is kind of the standard of care in this patient population. The Corcept regimen does require that.

最後，我們還努力開發一種不需要生長因子支持的預防性治療方案，這是該患者群體的護理標準。 Corcept 方案確實需要這樣做。

However, in their control arm that only got the Abraxane, only half the patients got G-CSF versus 100% on the experimental arm. So we don't -- we think that the 2 studies, really, can't be compared side by side because of the difference in patient populations and how they were treated.

然而，在只接受 Abraxane 的對照組中，只有一半的患者獲得了 G-CSF，而實驗組的這一比例為 100%。所以我們不認為——我們認為這兩項研究實際上不能並列比較，因為患者群體及其治療方式存在差異。

Yes. So I'm just adding to what Pratik mentioned, I think we, very deliberately, set ourselves up for a high bar to find signal, in terms of taking on a late-line patient population. But that was important for a combination regimen in a single-arm study. We had to set that kind of a high bar, so that we could clearly call the question of whether or not there was signal.

是的。因此，我只是補充普拉蒂克提到的內容，我認為我們非常刻意地為自己設定了一個高標準，以尋找信號，以應對晚期患者群體。但這對於單臂研究中的聯合治療方案很重要。我們必須設定一個很高的標準，這樣我們才能清楚地提出有沒有信號的問題。

And in terms of managing our resources prudently, that's why we did that, so that we can make this decision as quickly as possible, and that's why we've come to the conclusion that we did today.

在謹慎管理我們的資源方面，這就是我們這樣做的原因，以便我們能夠盡快做出這個決定，這就是為什麼我們得出今天所做的結論。

And a separate point, as Pratik mentioned about the use of G-CSF, we felt that it was pretty important, from both a patient care perspective as well as just what would be commercially viable, to be able to thread that needle without G-CSF. So again, that was an explicit decision that we made in charting out a longer-term potential path here.

還有一點，正如 Pratik 提到的關於 G-CSF 的使用，我們認為從患者護理的角度以及商業上可行的角度來看，能夠在沒有 G-CSF 的情況下穿針是非常重要的-腦脊液。再說一遍，這是我們在製定長期潛在路徑時做出的明確決定。

Our next question will come from the line of Kevin DeGeeter from Oppenheimer.

我們的下一個問題將來自奧本海默的凱文·德吉特（Kevin DeGeeter）。

Appreciate the really transparent release today. Pratik, in the interest of transparency, can you just comment on the tumor-agnostic basket? Any findings in there that you think could be hypothesis-generating for others who may explore the field subsequently?

感謝今天真正透明的發布。 Pratik，為了透明起見，您能評論一下與腫瘤無關的籃子嗎？您認為其中的任何發現可以為隨後可能探索該領域的其他人提供假設嗎？

Sure. Happy to do so. So we did have -- we treated 20 patients across 7 tumor types in that other tumor basket, and we saw one partial response in a patient with esophageal cancer and nothing else.

當然。很高興這樣做。所以我們確實治療了另一個腫瘤籃中 7 種腫瘤類型的 20 名患者，我們在一名食道癌患者中看到了部分反應，除此之外沒有其他反應。

Got it. And then, with regard to the PLK4 program, can you just talk a little bit about target product profile there, in terms of selectivity of the compound for PLK4, and just how we sort of think about breast cancer as the optimal population to explore that hypothesis?

知道了。然後，關於 PLK4 項目，您能否簡單談談那裡的目標產品概況，包括化合物對 PLK4 的選擇性，以及我們如何將乳腺癌視為探索該項目的最佳人群。假設？

Yes, Kevin, I can talk at a very high level about it, just because I don't want to front-run the preclinical poster we've got coming out of ACR here in a couple of weeks.

是的，Kevin，我可以在非常高的層面上談論這個問題，只是因為我不想搶先展示幾週後 ACR 發布的臨床前海報。

But essentially, the TPP is aiming to be very potent and very selective. It is a key synthetic-lethality pathway, and it's in the tumor type that's of high interest to us in breast cancer.

但本質上，TPP 的目標是非常有效且非常有選擇性。它是一個關鍵的合成致死途徑，並且它屬於我們對乳腺癌高度感興趣的腫瘤類型。

So it fits with everything else that we do and like target-wise, internally. But I'd ask you to maybe hold off for a few weeks or a month or so here until we present the poster at ACR. And then we can get into more detail on that.

因此，它與我們在內部所做的和喜歡的目標方面的其他一切都相符。但我想請您推遲幾週或一個月左右，直到我們在 ACR 上展示海報。然後我們可以更詳細地討論這一點。

Our next question come line of Colleen Kusy from Baird.

我們的下一個問題來自貝爾德 (Baird) 的科琳·庫西 (Colleen Kusy)。

So first one on ORIC-101 in prostate. I think at the last update at the Triple Conference, you had 4 patients that were still on treatment at that time. Do you have any update on what their time-on-treatment was?

第一個是關於前列腺中的 ORIC-101。我想在三重會議的最後一次更新中，當時有 4 名患者仍在接受治療。您有關於他們的治療時間的最新信息嗎？

Yes. So we had 6 patients in that bucket at the time, and 4 were ongoing at the time of the Triple Conference presentation. They have all since progressed, based on radiographic progression. Their time on treatment, 2 are 3.7 months, one at 7.1 months, and one at 9.2 months. So they all have come off since that presentation.

是的。因此，當時我們有 6 名患者，其中 4 名患者在三重會議演講時正在進行中。根據放射學進展，他們都取得了進展。他們的治療時間中，2 名患者的治療時間為 3.7 個月，1 名患者的治療時間為 7.1 個月，1 名患者的治療時間為 9.2 個月。所以自從那次演講之後，他們都消失了。

Okay. That's helpful. And you had made a comment in the presentation about how the PFS for the selected patients and unselected patients were similar. How should we understand what the outcome was there?

好的。這很有幫助。您在演示文稿中評論了選定患者和未選定患者的 PFS 有何相似之處。我們應該如何理解結果是什麼？

Sure, no. That's a good question. Let me, sort of, expand on that. The patients with the AR resistance variants and the lineage plasticity markers, did progress very rapidly. So these were the patients who had signs of their tumor already being AR resistant.

當然不。這是個好問題。讓我稍微擴展一下這一點。具有 AR 抗性變異和譜係可塑性標記的患者確實進展非常迅速。這些患者的腫瘤已經出現 AR 耐藥跡象。

So enzalutamide and returning sensitivity of enzalutamide wasn't going to do -- provide any benefit to them. And so that was not part of our target patient population.

因此，恩雜魯胺和恩雜魯胺恢復敏感性不會給他們帶來任何好處。因此，這不屬於我們的目標患者群體。

And so when we did exclude them, that did push up the PFS of the remaining group. And so then we subsetted the remaining patients by baseline GR expression status because we're interested in the patients who had high GR expression.

因此，當我們排除他們時，確實提高了剩餘組的 PFS。然後我們根據基線 GR 表達狀態對剩餘患者進行子集分組，因為我們對 GR 表達高的患者感興趣。

But there were patients for whom we did not have information on GR expression. And the reason was that there were no tumor cells in their biopsy specimen. And this group had a relatively longer PFS, and it's likely because they had an overall lower tumor burden.

但有些患者我們沒有 GR 表達的信息。原因是他們的活檢標本中沒有腫瘤細胞。該組的 PFS 相對較長，這可能是因為他們的腫瘤負荷總體較低。

So when we remove the GR unknown group, the PFS in the GR High group went back down. And so that's why we, overall, didn't see a difference between the 2, selected and unselected populations.

因此，當我們刪除 GR 未知組時，GR 高組中的 PFS 又下降了。因此，這就是為什麼我們總體上沒有看到選定群體和未選定群體之間存在差異。

That's interesting. And last one for me. I think prostate is also going to be a focus for ORIC-944. So are there any learnings you think you can take from this development and, kind of, apply that to future trials of prostate cancer?

那很有意思。最後一張給我。我認為前列腺也將成為 ORIC-944 的重點。那麼，您認為您可以從這一發展中學到什麼，並將其應用到未來的前列腺癌試驗中嗎？

Sure. So this is an entirely different target. And rather than reversing resistance of 944, has the potential for single-agent activity, and we've demonstrated that in multiple enzalutamide-resistant prostate cancer models.

當然。所以這是一個完全不同的目標。與逆轉 944 的耐藥性不同，它具有單藥活性的潛力，我們已經在多種恩雜魯胺耐藥性前列腺癌模型中證明了這一點。

This is something we didn't have with ORIC-101, which, going into the clinic, didn't have the potential for single-agent activity.

這是我們的 ORIC-101 所沒有的，它進入臨床後不具備單藥活性的潛力。

In addition, EED inhibition represents a novel mechanism of action, and it's relevant while tumor -- as tumors evolve. While for ORIC-101, we were essentially trying to revive enzalutamide activity, a mechanism which the cell had already become resistant to.

此外，EED 抑制代表了一種新的作用機制，並且隨著腫瘤的發展，它與腫瘤相關。而對於 ORIC-101，我們本質上是試圖恢復恩雜魯胺活性，這是細胞已經產生抗藥性的機制。

So we think that EED is taking, sort of, a fresh pass at the cancer cell. And despite the fact that there are potential resistance mechanisms in these late-line patients, EED would be novel for those cells and potentially clinically active.

因此，我們認為 EED 正在對癌細胞進行一次新的攻擊。儘管這些晚期患者存在潛在的耐藥機制，但 EED 對於這些細胞來說是新穎的，並且具有潛在的臨床活性。

That said, we do have, as we had in our ORIC-101 studies, an extensive translational component to look at tumor heterogeneity and other resistance mechanisms, so we can characterize the patients on study more fully and to potentially come up with a target patient subset that would be more amenable to EED inhibition.

也就是說，正如我們在 ORIC-101 研究中所做的那樣，我們確實擁有廣泛的轉化組件來研究腫瘤異質性和其他耐藥機制，因此我們可以更全面地描述研究中患者的特徵，並有可能提出目標患者更容易受到 EED 抑制的子集。

Our next question is come from the line of Maury Raycroft from Jefferies.

我們的下一個問題來自 Jefferies 的莫里·雷克羅夫特 (Maury Raycroft)。

I was going to ask one on ORIC-101 and then one on 533. I guess, for 101, can you expand on what you saw with tumor heterogeneity and discuss an example of tumor heterogeneity observed in the study?

我本來想問一個關於 ORIC-101 的問題，然後又問一個關於 533 的問題。我想，對於 101，您能否擴展您所看到的腫瘤異質性並討論在研究中觀察到的腫瘤異質性的一個例子？

Sure. So we probably have the best data from the prostate study. We were able to do baseline and on-study biopsies, as well as circulating tumor DNA profiling, so we could watch the tumors evolve while the patients were on the study.

當然。所以我們可能擁有前列腺研究的最佳數據。我們能夠進行基線和研究中的活檢，以及循環腫瘤 DNA 分析，因此我們可以在患者參與研究時觀察腫瘤的演變。

And so in that trial, we saw multiple examples of patients who, despite being within our target patient population, so they did not have AR resistance variants or markers of lineage plasticity and were GR high at baseline, they gained one or more of these resistance mechanisms or other potential resistance factors while on study, such as gaining ARv7 or [MEK] or a loss of p10 or Tp53.

因此，在那次試驗中，我們看到了多個患者的例子，儘管他們屬於我們的目標患者群體，因此他們沒有 AR 耐藥變異或譜係可塑性標記，並且在基線時 GR 高，但他們獲得了一種或多種這些耐藥性研究期間的機製或其他潛在耐藥因素，例如獲得 ARv7 或 [MEK] 或 p10 或 Tp53 的損失。

And some of these patients, these alternate clones, were minor at baseline but grew while on study. And so that was the heterogeneity and a redundant resistance mechanisms I was referring to earlier.

其中一些患者，這些替代克隆，在基線時身材較小，但在研究過程中不斷成長。這就是我之前提到的異質性和多餘的抵抗機制。

Got it. Okay. Interesting. And for 533, the monotherapy data in a triple-class refractory myeloma that's not expected until first half of '23. But can you comment, if you're in discussions with pharma partners to evaluate combo regimens in myeloma and other tumor types run in parallel?

知道了。好的。有趣的。對於 533，三級難治性骨髓瘤的單一療法數據預計要到 23 年上半年才會出現。但是，如果您正在與製藥合作夥伴討論評估骨髓瘤和其他腫瘤類型並行運行的組合方案，您能發表評論嗎？

Maury, this is Jacob. I can't comment specifically, but I'll just tell you generically that we have lots of conversations along those lines with lots of pharma partners on the various programs in our pipeline. But we don't really comment on specific discussions of individual programs.

莫里，這是雅各布。我無法具體發表評論，但我只是籠統地告訴您，我們與許多製藥合作夥伴就我們管道中的各種項目進行了很多對話。但我們並不真正評論個別節目的具體討論。

Got it. And for combo strategy, is there anything additional you're seeing at this point on that?

知道了。對於組合策略，您目前還看到了什麼其他內容嗎？

The one thing, and I think your question highlights it is, we're absolutely of the mindset that for 533, we're not planning to run out a single-agent trial over a long period of time and then decide at that point whether we're going to greenlight a combo or not.

我認為你的問題強調了這一點，我們絕對認為對於 533，我們不打算在很長一段時間內進行單藥試驗，然後在那時決定是否我們是否會批准組合。

It's pretty clear here that in that triple-quad, penta-refractory population, if we see even modest activity as a single agent, then we got to quickly explore that in combinations.

很明顯，在三重四重、五重難治性人群中，如果我們看到單一藥物的哪怕是適度的活動，那麼我們就必須快速探索其組合。

And you'll remember that Ken Anderson in the call that we hosted in December at ASH, Dr. Anderson mentioned exactly that point that as soon as you see modest single-agent activity, you ought to test combinations.

您會記得 Ken Anderson 在我們 12 月份在 ASH 舉辦的電話會議中，Anderson 博士準確地提到了這一點，即一旦您看到適度的單一藥物活動，您就應該測試組合。

You probably ought to test multiple combinations, in terms of combination partners, meaning that the preclinical models don't give you great evidence of one specific combo class to combine with.

您可能應該在組合夥伴方面測試多種組合，這意味著臨床前模型不會為您提供要結合的特定組合類別的有力證據。

So we probably will combine with a multiple of the combination classes that you might think of doing. And we would do that pretty much -- I mean, almost in parallel with the single-agent studies that are going on, provided that we've seen that modest activity that I mentioned.

因此，我們可能會結合您可能想到的多個組合類。我們幾乎會這樣做——我的意思是，幾乎與正在進行的單藥研究同時進行，前提是我們已經看到了我提到的適度活動。

I think that's where you were driving with your question about conversations we may or may not be having.

我認為這就是您提出有關我們可能進行或不進行對話的問題的地方。

Our next question in comes from the line of Yigal Nochomovitz from Citigroup.

我們的下一個問題來自花旗集團的 Yigal Nochomovitz。

This is Ashiq Mubarack for Yigal. Sorry to hear about the discontinuation. I think you alluded to this in the previous question, but can you discuss a little more what secondary pathways of resistance you're hypothesizing may have contributed to the lack of resensitization?

我是伊加爾的阿希克·穆巴拉克。很遺憾聽到有關停產的消息。我想您在上一個問題中提到了這一點，但是您能否多討論一下您假設的哪些次要抵抗途徑可能導致缺乏重新敏化？

So some of these were ones that we screened out at baseline but developed while on study. So ARv7 would be a resistance pathway that secondary alternate -- that GR inhibition wouldn't address that. p10 loss, Tp53 loss are also associated with resistance. So those are the other mechanisms that we saw. And we saw others as well. Those were examples.

因此，其中一些是我們在基線時篩選出來的，但在研究過程中開發出來的。因此，ARv7 將是次要替代的耐藥途徑——GR 抑制無法解決這個問題。 p10缺失、Tp53缺失也與耐藥相關。這些是我們看到的其他機制。我們也看到了其他人。這些都是例子。

Okay. Got it. And then maybe switching to the CD73. Have you guided to when you expect to complete enrollment in the Phase Ib? And maybe what does that imply about what kind of follow-up you might present next year?

好的。知道了。然後可能會切換到 CD73。您是否已指導您預計何時完成 Ib 階段的註冊？也許這對你明年可能會推出什麼樣的後續作品意味著什麼？

We haven't guided at this point. It's just too early, just given that the trial initiated, literally, this quarter. So we have not provided that guidance yet.

我們目前還沒有指導。現在還為時過早，因為試驗實際上是在本季度開始的。所以我們還沒有提供該指導。

Our next question will be from the line of Michael Schmidt from Guggenheim.

我們的下一個問題將來自古根海姆的邁克爾·施密特。

This is Yige on for Michael. Two questions on your pipeline programs. The first one on your new PLK4 program. Can you maybe help us understand the opportunity and the size of the TRIM37 amplification?

這是邁克爾的易格。關於您的管道計劃的兩個問題。新 PLK4 程序中的第一個。您能否幫助我們了解 TRIM37 放大的機會和規模？

And secondly, on 114, you initiated the Phase I study. Help us understand, how you plan to measure 114 CNS activity in the Phase I study? And will you plan to enroll active brain met patients in the future?

其次，在114，你們啟動了第一階段研究。請幫助我們了解，您計劃如何在 I 期研究中測量 114 CNS 活動？您將來是否計劃招募活躍的大腦遇見患者？

I'll take the first, and I'll ask Pratik to take the second. So on the first, as I mentioned earlier to Kevin, we probably -- we've got a poster coming up at ACR on PLK4. So I'd probably defer the specific answers around market size and just differentiation until then.

我會選擇第一個，我會請普拉蒂克選擇第二個。因此，首先，正如我之前向 Kevin 提到的，我們可能會在 ACR 的 PLK4 上發布一張海報。因此，我可能會將有關市場規模和差異化的具體答案推遲到那時。

I think the main thing to point out on PLK4 is, it's totally consistent with what our strategy has been from the beginning. We plan to put forward programs that are both from our internal discovery programs as well as through external, opportunistic BD. In this case, it's one that came from our internal discovery efforts, single-agent potential mechanism of action.

我認為關於 PLK4 需要指出的主要一點是，它與我們從一開始就制定的策略完全一致。我們計劃提出的計劃既來自我們的內部發現計劃，也來自外部的機會主義 BD。在這種情況下，它來自我們內部的發現工作，即單劑潛在的作用機制。

Like I said, a synthetic-lethality pathway that's relevant to breast cancer, plus a couple of other tumor types. And importantly, and we've been explicit about this as well, is we've always wanted our pipeline to have a mix of first-in-class targets that rely on differentiated biological insights and then potentially best-in-class targets that rely on chemistry or biological insights.

就像我說的，一種與乳腺癌以及其他幾種腫瘤類型相關的合成致死途徑。重要的是，我們也明確指出了這一點，我們一直希望我們的管道能夠擁有依賴於差異化生物學見解的一流目標和依賴於差異化生物學見解的潛在一流目標的組合。關於化學或生物學的見解。

And in this case, this is, we believe, a potentially first-in-class opportunity. Our team got to jump on this target a while back, ahead of a paper that was published in nature that came out last year.

在這種情況下，我們相信，這是一個潛在的一流機會。我們的團隊不久前就開始實現這個目標，領先於去年發表在《自然》雜誌上的一篇論文。

And so we're pretty excited about it because it's a potentially first-in-class opportunity, like I said, with a single-agent hypothesis in the tumor type that we care a lot about. So stay tuned for the poster at ACR, and then we can get into more specifics at that point.

因此，我們對此感到非常興奮，因為正如我所說，這是一個潛在的一流機會，在我們非常關心的腫瘤類型中提出了單藥假設。請繼續關注 ACR 的海報，屆時我們可以了解更多細節。

This is Pratik. To your question about 114 and CNS activity. So we are more liberal in our Phase I eligibility criteria, in terms of allowing patients into the study, not just with treated and stable brain mets, which is what most other studies allow but also allowing patients with active brain mets as well that are asymptomatic. So we are allowing untreated brain mets into even our Phase I...

這是普拉蒂克。關於您關於 114 和中樞神經系統活動的問題。因此，我們在第一階段的資格標准上更加自由，允許患者參與研究，不僅允許接受治療且穩定的腦代謝物（這是大多數其他研究所允許的），而且還允許患有活躍腦代謝物以及無症狀的患者。因此，我們甚至允許未經治療的腦代謝綜合徵進入第一階段……

I'm not showing any further questions in the queue. That will conclude our conference call for today. Thank you so much for your participation and your interest in ORIC. You may now disconnect. Everyone, have a great day.

我不會在隊列中顯示任何其他問題。我們今天的電話會議到此結束。非常感謝您的參與以及對 ORIC 的關注。您現在可以斷開連接。大家，祝你有美好的一天。