Gritstone bio Inc (GRTS) 2024 Q1 法說會逐字稿

Greetings. My name is Latonya, and welcome to the Gritstone bio's first-quarter 2024 conference call. Please note this event is being recorded.

問候。我叫 Latonya，歡迎參加 Gritstone Bio 2024 年第一季電話會議。請注意此事件正在被記錄。

At this time, I'd like to introduce George McDougall, Head of Investor Relations and Corporate Communications at Gritstone. Please go ahead, sir.

這次，我想介紹 Gritstone 投資人關係和企業傳播主管 George McDougall。請繼續，先生。

Thank you, Latonya, and thank you, everyone, for joining Gritstone conference call to discuss our financial results, clinical, and business updates for the first quarter of 2024.

謝謝 Latonya，也謝謝大家參加 Gritstone 電話會議，討論我們 2024 年第一季的財務表現、臨床和業務更新。

With me on the call today from Gritstone are Andrew Allen, Co-Founder, President, and CEO; Celia Economides, Executive Vice President and Chief Financial Officer. And joining us for the Q&A portion will be Karin Jooss, Executive Vice President and Head of R&D.

今天與我一起參加 Gritstone 電話會議的是共同創辦人、總裁兼執行長 Andrew Allen； Celia Economides，執行副總裁兼財務長。執行副總裁兼研發主管 Karin Jooss 將加入我們的問答部分。

Today, after the market closed, we issued a press release providing corporate updates and financial results for the first quarter of 2024. The press release is available on our website.

今天，市場收盤後，我們發布了一份新聞稿，提供 2024 年第一季的公司最新情況和財務表現。新聞稿可在我們的網站上取得。

I'd like to remind you again that today's call is being webcast live via a link on Gritstone's Investor Relations website, where a replay will also be available after its completion. After our prepared remarks, we will open up the call for Q&A.

我想再次提醒您，今天的電話會議將透過 Gritstone 投資者關係網站上的連結進行網路直播，會議結束後也將提供重播。在我們準備好發言後，我們將開放問答環節。

During the course of this call, we will make forward-looking statements that are based on current expectations. These forward-looking statements are subject to a number of significant risks and uncertainties, and actual results may differ materially from those that are discussed. We encourage you to review the risk factors in our most recent Form 10-Q with the US Securities and Exchange Commission and is also available on our website.

在本次電話會議期間，我們將根據目前預期做出前瞻性陳述。這些前瞻性陳述面臨許多重大風險和不確定性，實際結果可能與討論的結果有重大差異。我們鼓勵您查看我們向美國證券交易委員會提交的最新 10-Q 表中的風險因素，該表也可在我們的網站上取得。

All statements on this call are made as of today based on information currently available to us. Except as required by law, we disclaim any obligation to update such statements even if our views change. Gritstone hosts these calls on an ad hoc basis, and we hope you'll find today's call useful.

本次電話會議的所有聲明均基於我們目前掌握的資訊。除非法律要求，否則即使我們的觀點發生變化，我們也不承擔更新此類聲明的義務。Gritstone 會暫時主持這些電話會議，我們希望今天的電話會議對您有所幫助。

With that, let me turn it over to Andrew. Andrew?

那麼，讓我把它交給安德魯。安德魯？

Thank you, George, and good afternoon, everybody, and thank you for joining our first-quarter 2024 conference call. This is a very exciting time for Gritstone, and I'll begin today's call with a review of our most recent data from our personalized cancer vaccine program GRANITE, as well as provide other clinical and corporate updates. Then Celia will present the financials and I'll come back to share closing remarks.

謝謝喬治，大家下午好，謝謝您參加我們的 2024 年第一季電話會議。對於 Gritstone 來說，這是一個非常令人興奮的時刻，我將在今天的電話會議開始時回顧我們個人化癌症疫苗計畫 GRANITE 的最新數據，並提供其他臨床和公司最新資訊。然後西莉亞將介紹財務狀況，我將回來分享結束語。

Okay, let's get going. So we recently shared preliminary data from our randomized Phase 2 study of GRANITE in frontline metastatic microsatellite-stable colorectal cancer patients. These early data are highly encouraging, and they suggest that our personalized neoantigen vaccine is inducing therapeutically beneficial immune responses in the 67 patients included in our preliminary dataset.

好的，我們開始吧。因此，我們最近分享了 GRANITE 在一線轉移性微衛星穩定大腸直腸癌患者中的隨機 2 期研究的初步數據。這些早期數據非常令人鼓舞，它們表明我們的個人化新抗原疫苗正在我們初步數據集中的 67 名患者中誘導治療上有益的免疫反應。

Let's review what we showed. Firstly, the patients we're treating in this study are typical colorectal cancer patients. Approximately 75% of them have liver metastases and approximately half of them have KRAS mutations.

讓我們回顧一下我們所展​​示的內容。首先，我們本研究中治療的患者是典型的大腸直腸癌患者。其中約 75% 有肝轉移，其中約一半有 KRAS 突變。

In terms of efficacy, we observed a trend towards progression-free survival, or PFS benefit, with a hazard ratio in the overall population of 0.82. Median progression-free survival, or PFS, in this indication is approximately 11 months. The last patient randomized in this study entered in August 2023 and these data were cut in early March 2024, meaning that last patient was on the study for only approximately eight months, obviously short of the median PFS of 11 months.

就療效而言，我們觀察到無惡化存活期或 PFS 獲益的趨勢，整體族群的風險比為 0.82。此適應症的中位無惡化存活期 (PFS) 約為 11 個月。本研究中最後一位隨機入組的患者於2023 年8 月進入，這些數據於2024 年3 月初被削減，這意味著最後一位患者僅參與研究約8 個月，明顯低於11 個月的中位PFS。

That renders these data rather immature. But even though these data are preliminary, with over 60% censoring, meaning that over 60% of patients have not yet achieved an event of progression or death, this is a promising signal. As you may know, a hazard ratio of less than 1 implies a treatment benefit. And the lower the hazard ratio, the stronger the treatment effect, i.e., the greater the benefit.

這使得這些數據相當不成熟。但儘管這些數據是初步數據，有超過 60% 的審查，這意味著超過 60% 的患者尚未出現進展或死亡事件，但這仍然是一個有希望的信號。如您所知，風險比小於 1 意味著治療有益。且風險比越低，治療效果越強，即獲益越大。

Now, to get a better understanding of what outcomes we may see as the overall dataset matures, we identified at baseline prior to therapy a subset of patients that would be likely to progress faster than the overall population. Nearly all of these patients, and we refer to them as high risk, had liver metastases. As expected, the PFS data in this group were more mature with 44% censoring.

現在，為了更好地了解隨著整個數據集的成熟我們可能會看到什麼結果，我們在治療前在基線處確定了可能比總體人群進展更快的患者子集。幾乎所有這些患者（我們稱之為高風險患者）都患有肝轉移。正如預期的那樣，該組的 PFS 數據更加成熟，有 44% 的審查。

And the apparent PFS benefit associated with GRANITE therapy was much stronger in this high-risk population than in the overall population. We reported a hazard ratio of 0.52, which is striking and equates to a 48% relative risk reduction of progression or death with GRANITE versus control.

在這個高風險族群中，與 GRANITE 治療相關的明顯 PFS 益處比在整體人群中要強得多。我們報告的風險比為 0.52，這是驚人的，相當於 GRANITE 與對照組相比，進展或死亡的相對風險降低了 48%。

The early data in these high-risk patients who give us information faster give us a potential window into the future. And as our data mature, meaning more patients experience disease progression, we expect the clinical benefits of GRANITE versus standard of care to become more pronounced. We're excited to share the mature PFS data on all patients in the third quarter of 2024, and then we plan to discuss the final Phase 3 endpoints with the FDA.

這些高風險患者的早期數據可以更快地為我們提供信息，為我們提供了通往未來的潛在窗口。隨著我們數據的成熟，意味著更多患者會出現疾病進展，我們預計 GRANITE 相對於標準護理的臨床益處將變得更加明顯。我們很高興在 2024 年第三季分享所有患者的成熟 PFS 數據，然後我們計劃與 FDA 討論最終的 3 期終點。

The encouraging PFS data at this early timepoint are important. PFS has historically been a proxy for overall survival in this disease and has therefore been used by regulatory authorities as the basis for approval of novel therapies. Previously, we've been cautious about PFS as an efficacy endpoint, given the potential for pseudoprogression with immunotherapy. Pseudoprogression is a phenomenon where lesions actually grow at the beginning of treatment prior to shrinking, which can lead to the attendant risk of patients being incorrectly labeled as having progressive disease.

在這個早期時間點令人鼓舞的 PFS 數據非常重要。PFS 歷史上一直是該疾病整體存活率的指標，因此已被監管機構用作批准新療法的基礎。先前，考慮到免疫療法可能出現假性進展，我們對 PFS 作為療效終點持謹慎態度。假性進展是一種病灶在治療開始時實際上在縮小之前生長的現象，這可能導致患者被錯誤地標記為患有進行性疾病的風險。

To date, we have seen no evidence of pseudoprogression in our Phase 2 study, which supports the use of PFS as a Phase 3 efficacy endpoint, perhaps as the basis for approval. And this topic will be discussed with FDA at our end of Phase 2 meeting.

迄今為止，我們在 2 期研究中尚未發現假性進展的證據，該研究支持使用 PFS 作為 3 期療效終點，或許可以作為批准的基礎。我們將在第二階段會議結束時與 FDA 討論這個主題。

It's also worth noting, we've seen apparent extension of PFS with GRANITE before. We observed PFS and OS extension in third-line colorectal cancer patients treated in our Phase 1/2 study of GRANITE, wherein the 50% or so of patients with biochemical and molecular responses to GRANITE, meaning reductions in tumor markers, we saw extended PFS and OS compared with the non-responding patients. The interim data from this Phase 1/2 were published in Nature Medicine in 2022.

還值得注意的是，我們之前已經看到 GRANITE 的 PFS 明顯延長。我們在GRANITE 的1/2 期研究中觀察到接受治療的三線結直腸癌患者的PFS 和OS 延長，其中約50% 的患者對GRANITE 產生生化和分子反應，這意味著腫瘤標記減少，我們看到PFS 延長和 OS 與無反應患者相比。1/2 期的中期數據於 2022 年發表於《自然醫學》。

And recall that we also saw similar signals of apparently extended OS, again, linked to biochemical and molecular responses in a Phase 1/2 study of SLATE, our off-the-shelf cancer vaccine that uses the same platform technologies as GRANITE. But this was in patients with advanced non-small cell and microsatellite-stable colorectal cancer.

回想一下，我們在 SLATE 的 1/2 期研究中也看到了明顯延長的 OS 的類似訊號，與生化和分子反應有關，SLATE 是我們現成的癌症疫苗，使用與 GRANITE 相同的平台技術。但這是針對晚期非小細胞和微衛星穩定大腸直腸癌的患者。

The fact that we are seeing these concordant signals across different studies, different settings, and different disease types gives us further confidence that granite could be driving meaningful clinical benefit. Now, to limit the potential impacts of pseudo progression, we set PFS as the first secondary efficacy endpoint for our Phase 2 trial. And the primary endpoint was set as molecular response, a specific method of measuring change in circulating tumor DNA, which I'll abbreviate to ctDNA.

事實上，我們在不同的研究、不同的環境和不同的疾病類型中看到這些一致的訊號，這讓我們進一步相信花崗岩可以帶來有意義的臨床效益。現在，為了限制假性進展的潛在影響，我們將 PFS 設定為 2 期試驗的第一個次要療效終點。主要終點被設定為分子反應，這是一種測量循環腫瘤 DNA 變化的特定方法，我將其縮寫為 ctDNA。

And this was based on what we'd seen in Phase 1/2. And of course, there were no controls in that study. So therefore, we had to make an assumption about how chemotherapy would affect ctDNA going into this study. And what we observed is that chemo actually has an unexpectedly prolonged effect, rendering a single timepoint definition of ctDNA response, which is what we used unreflective of clinical benefit.

這是基於我們在第 1/2 階段看到的情況。當然，該研究中沒有對照。因此，在本研究中，我們必須假設化療將如何影響 ctDNA。我們觀察到，化療實際上具有意想不到的長期效果，從而呈現出 ctDNA 反應的單一時間點定義，而這正是我們所使用的並不能反映臨床益處的方法。

Now, importantly, when we look at ctDNA trends across the entire study period, we see broad evidence that GRANITE patients are indeed experiencing greater reductions in ctDNA versus those in the control group. This finding is consistent with the PFS signal. So the data emerging from the randomized Phase 2 of our GRANITE trial build upon what we observed in the Phase 1/2 trial and suggest that Granite neoantigen-directed immunotherapy could deliver strong PFS result in metastatic colorectal cancer patients in a few months time. And again, we expect those mature data in the third quarter of this year.

現在，重要的是，當我們觀察整個研究期間的 ctDNA 趨勢時，我們看到廣泛的證據表明，與對照組相比，GRANITE 患者的 ctDNA 確實出現了更大的減少。這項發現與 PFS 訊號一致。因此，GRANITE 隨機2 期試驗的數據建立在我們在1/2 期試驗中觀察到的數據的基礎上，表明Granite 新抗原導向的免疫療法可以在幾個月內為轉移性結直腸癌患者帶來良好的PFS 結果。我們再次預計這些成熟數據將在今年第三季公佈。

But why would positive data be significant for patients? Because colorectal cancer is now the leading and second leading cause of US cancer deaths in males and females under 50, respectively, in addition to being the second leading cause of cancer mortality worldwide. Microsatellite-stable tumors comprise about 95% of all metastatic colorectal cancer diagnoses, and treatment options are few, with no approved immunotherapies for this highly resistant cold tumor. A positive randomized trial result would therefore offer desperately needed hope for one of the largest and most underserved solid tumor communities worldwide.

但為什麼陽性數據對患者來說意義重大呢？因為大腸癌現在分別是美國 50 歲以下男性和女性癌症死亡的第一大和第二大原因，也是全球癌症死亡的第二大原因。微衛星穩定腫瘤約佔所有轉移性大腸直腸癌診斷的 95%，治療選擇很少，目前還沒有針對這種高度抗藥性的冷腫瘤的批准的免疫療法。因此，積極的隨機試驗結果將為全球最大、服務最匱乏的實體瘤社區之一帶來迫切需要的希望。

Why would positive granite data be significant for the field? Because immunotherapy is generally believed to be ineffective in so-called cold tumors, such as microsatellite-stable colorectal cancer and since checkpoint inhibitor therapy alone has not delivered benefit in this setting.

為什麼積極的花崗岩數據對該領域具有重要意義？因為免疫療法通常被認為對所謂的冷腫瘤（例如微衛星穩定的結直腸癌）無效，而且單獨的檢查點抑制劑療法在這種情況下無法帶來好處。

To date, to our knowledge, all of our neoantigen-directed personalized cancer vaccine competitors have studied cold metastatic tumors and have reported little to no signal of efficacy with their platforms, hence their current focus on adjuvant indications and/or hot tumors. Success for GRANITE in a cold metastatic tumor could open the door for effective immunotherapy to the majority of solid tumor patients, both in metastatic and adjuvant settings, a potentially dramatic expansion of the overall opportunity.

到目前為止，據我們所知，我們所有的新抗原導向的個人化癌症疫苗競爭對手都研究了冷轉移腫瘤，並且幾乎沒有報告其平台的功效信號，因此他們目前的重點是輔助適應症和/或熱腫瘤。GRANITE 在冷轉移腫瘤中的成功可能為大多數實體腫瘤患者（無論是在轉移性腫瘤還是輔助治療中）打開有效免疫療法的大門，這可能會顯著擴大整體機會。

And finally, why would positive mature PFS data be meaningful for Gritstone? Because, of course, it suggests potential for a big opportunity immediately ahead of us in metastatic colorectal cancer, and that our objective of unlocking the broad set of immunologically cold tumors may be within reach.

最後，為什麼積極的成熟 PFS 數據對 Gritstone 有意義？當然，因為它表明我們在轉移性結直腸癌方面面臨著巨大的機遇，並且我們解鎖廣泛的免疫冷腫瘤的目標可能是可以實現的。

Having PFS as a reliable early measure of the effectiveness of our therapy gives us a potentially faster regulatory path in colorectal cancer and any other indications we pursue. Expanding the scope of immunotherapy to a wide spectrum of cancer patients is the holy grail of immuno-oncology for good reason: it's challenging, and it's not been done before despite decades of effort.

將 PFS 作為衡量治療有效性的可靠早期指標，為我們在結直腸癌和我們追求的任何其他適應症方面提供了一條可能更快的監管路徑。將免疫療法的範圍擴大到廣泛的癌症患者是免疫腫瘤學的聖杯，這是有充分理由的：它具有挑戰性，儘管經過了數十年的努力，以前從未有人做到過。

Now, along with GRANITE, we continue advancing our other promising programs and platform technologies and we're attracting great recognition and support. The recent SLATE publication in Nature Medicine highlights the promise of our off-the-shelf platform for solid tumors, which we believe is ready for plug-and-play applications across a spectrum of solid tumors. This promise is underscored by the ongoing collaboration with Dr. Steven Rosenberg of the National Cancer Institutes to evaluate our mutant KRAS-directed vaccine candidate in combination with an autologous mutant KRAS-directed TCRT cell therapy.

現在，我們與 GRANITE 一起繼續推進其他有前途的計劃和平台技術，並且我們正在吸引巨大的認可和支援。最近在 Nature Medicine 上發表的 SLATE 文章強調了我們現成的實體瘤平台的前景，我們相信該平台已準備好在一系列實體瘤中進行即插即用應用。與美國國家癌症研究所的 Steven Rosenberg 博士持續合作，評估我們的突變 KRAS 導向候選疫苗與自體突變 KRAS 導向 TCRT 細胞療法的結合，強調了這一承諾。

The recent presentation of the latest improvements to EDGE, our state-of-the-art prediction platform that leverages artificial intelligence to identify the new antigen targets we encode in GRANITE, further underscores our leadership position in the field of neoantigen-directed cancer vaccines. EDGE now predicts HLA Class I presentation of epitopes with greater than 80% positive predictive value, performance well beyond that of public models. And it offers what we believe to be a leading technology within the field.

最近介紹了 EDGE 的最新改進，EDGE 是我們最先進的預測平台，利用人工智慧來識別我們在 GRANITE 中編碼的新抗原靶點，進一步凸顯了我們在新抗原導向癌症疫苗領域的領導地位。EDGE 現在預測 HLA I 類表位的呈現具有超過 80% 的陽性預測值，性能遠遠超出公共模型。它提供了我們認為是該領域領先的技術。

EDGE also now includes a comprehensive state-of-the-art model for predicting peptide presentation by HLA Class 2 in the context of active vaccination, which could serve to further strengthen T-cell responses to our novel vaccines. We were among the first players to leverage AI technology in this fashion and will continue to invest in EDGE to further what we believe to be a key potential strategic advantage.

EDGE 現在還包括一個最先進的綜合模型，用於預測主動疫苗接種背景下 HLA 2 類的勝肽呈現，這可以進一步增強 T 細胞對我們的新型疫苗的反應。我們是第一批以這種方式利用人工智慧技術的參與者之一，並將繼續投資 EDGE，以進一步推進我們認為的關鍵潛在策略優勢。

Beyond oncology, we continue pushing forward in infectious disease, largely leveraging external dollars. Our recent presentation at the ESCMID Conference reinforced previous Phase 1 findings and highlighted the durability and potential broad utility of our self-amplifying mRNA vaccine against COVID-19. The efforts and dialog with BARDA regarding running a Phase 2b head-to-head study in COVID-19 continue, and we remain very excited about this important 10,000-subject study.

除了腫瘤學之外，我們還在很大程度上利用外部資金繼續推動傳染病領域的發展。我們最近在 ESCMID 會議上的演講強化了先前第一階段的研究結果，並強調了我們針對 COVID-19 的自擴增 mRNA 疫苗的耐用性和潛在的廣泛用途。與 BARDA 關於進行 COVID-19 2b 期頭對頭研究的努力和對話仍在繼續，我們對這項重要的 10,000 名受試者研究仍然感到非常興奮。

Along with BARDA and others engaged in prophylaxis efforts, we've garnered support from other leading players, including Gilead Sciences, for its therapeutic vaccine for HIV. And we remain excited about the broad potential applicability of our capabilities and self-amplifying mRNA platform in infectious disease. As our data mature across our portfolio, we continue to execute on our mission of delivering the most potent and durable vaccines.

與 BARDA 和其他從事預防工作的機構一起，我們的 HIV 治療性疫苗獲得了包括吉利德科學公司在內的其他領先企業的支持。我們對我們的能力和自我放大 mRNA 平台在傳染病中的廣泛潛在適用性感到興奮。隨著我們的數據在我們的產品組合中不斷成熟，我們將繼續履行提供最有效、最持久的疫苗的使命。

Now, I'll turn over to Celia to speak to our financial position.

現在，我將請西莉亞談談我們的財務狀況。

Thank you, Andrew. Good afternoon, everyone. We ended the quarter with cash, cash equivalents, marketable securities, and restricted cash of $52.8 million. As you are aware, in April of 2024, we completed an underwritten public offering resulting in gross proceeds to Gritstone of $32.5 million, bringing our pro forma cash, cash equivalents, marketable securities, and restricted cash to approximately $85.3 million.

謝謝你，安德魯。大家下午好。本季末，我們的現金、現金等價物、有價證券和限制性現金為 5,280 萬美元。如您所知，2024 年 4 月，我們完成了承銷公開發行，Gritstone 的總收益為 3,250 萬美元，使我們的預計現金、現金等價物、有價證券和限制性現金達到約 8,530 萬美元。

In February, we made the difficult decision to reduce our workforce by approximately 40%. Combined, these actions have reduced our estimated quarterly cash burn rate and extended our runway into the fourth quarter of 2024.

2 月份，我們做出了艱難的決定，將員工人數減少約 40%。這些行動結合起來，降低了我們估計的季度現金消耗率，並將我們的跑道延長到 2024 年第四季。

As you know, our priority is driving the GRANITE program forward, and our OpEx reflects this. On the infectious disease side, to date, we have primarily funded our programs with non-dilutive outside capital.

如您所知，我們的首要任務是推動 GRANITE 計畫向前發展，我們的營運支出反映了這一點。在傳染病方面，迄今為止，我們主要使用非稀釋性外部資本為我們的專案提供資金。

Several of our long-standing infectious disease collaborations continue and could potentially serve to bring additional capital to the company. As we think about the next steps for our ID business, we are exploring strategic funding approaches to support our growing infectious disease programs and business. In addition to our current collaborations, new partnerships in both oncology and infectious disease could serve as additional sources of capital.

我們的一些長期傳染病合作仍在繼續，並有可能為公司帶來額外的資金。當我們考慮 ID 業務的下一步時，我們正在探索策略性融資方法來支持我們不斷增長的傳染病項目和業務。除了我們目前的合作之外，腫瘤學和傳染病領域的新合作夥伴關係也可以作為額外的資本來源。

Turning now to our Q1 2024 operating results. We reported a net loss of $40.4 million, compared with $34 million for the same period last year. The increase in our net loss is primarily attributable to the decrease in collaboration revenue of $0.7 million, an increase in research and development expenses of $2.5 million, and an increase in our G&A expenses of $1.8 million.

現在轉向我們 2024 年第一季的營運表現。我們報告的淨虧損為 4,040 萬美元，而去年同期為 3,400 萬美元。我們的淨虧損增加主要是因為合作收入減少 70 萬美元、研發費用增加 250 萬美元以及一般管理費用增加 180 萬美元。

The establishment of collaborations and partnerships is a core part of our business strategy as we continue to leverage our unique platforms and capabilities. Our collaboration license and grant revenue for the first quarter ending March 31, 2024 totaled $1.7 million. This is compared to $2.4 million for the same period in 2023.

隨著我們繼續利用我們獨特的平台和能力，建立合作和夥伴關係是我們業務策略的核心部分。截至 2024 年 3 月 31 日的第一季度，我們的合作許可和贈款收入總計 170 萬美元。相較之下，2023 年同期為 240 萬美元。

Our research and development expenses were $33 million for the three months ended March 31, 2024, compared with $30.5 million for the same period in 2023. The increase in R&D cost was primarily due to a one-time severance and impairment charge and increases in facilities related costs, which were partially offset by decreases in lab supplies, personnel-related costs, and outside services.

截至2024年3月31日止三個月，我們的研發費用為3,300萬美元，而2023年同期為3,050萬美元。研發成本的增加主要是由於一次性遣散費和減損費用以及設施相關成本的增加，但部分被實驗室用品、人員相關成本和外部服務的減少所抵消。

G&A expenses for the period were $8.5 million, up from $6.7 million for the same period last year. The increase in G&A expenses for the period ending March 31 was primarily attributable to personnel-related expenses, facilities-related costs, outside services, and a one-time severance charge.

該期間的一般管理費用為 850 萬美元，高於去年同期的 670 萬美元。截至 3 月 31 日的期間一般管理費用的增加主要歸因於人員相關費用、設施相關成本、外部服務和一次性遣散費。

As of March 31, 2024, Gritstone had approximately 97.6 million shares of common stock outstanding, prefunded warrants outstanding to purchase approximately 7.2 million shares of common stock at a nominal exercise price of $0.01 per share, and approximately 13.3 million shares of common stock at a nominal exercise price of $0.0001 per share.

截至2024 年3 月31 日，Gritstone 擁有約9,760 萬股已發行普通股、已發行預融資認股權證，可依名目行使價每股0.01 美元購買約720 萬股普通股，以及以每股名義行使價購買約1330 萬股普通股。

In summary, we are confident in our ability to execute on our strategic objectives and toward our growth inflection points.

總之，我們對執行策略目標和實現成長拐點的能力充滿信心。

I'll now turn the call back over to Andrew for some closing remarks.

現在我將把電話轉回給安德魯，讓他做一些結束語。

Thanks, Celia. We started Gritstone to expand the emerging benefits of immunotherapy to all patients with solid tumors, and we're unwavering in our focus on that critical goal and very pleased with the progress we've made supporting the potential for neoantigen-based cancer vaccines.

謝謝，西莉亞。我們創辦Gritstone 的目的是為了將免疫療法的新優勢擴大到所有實體瘤患者，我們堅定不移地專注於這一關鍵目標，並對我們在支持基於新抗原的癌症疫苗潛力方面取得的進展感到非常高興。

Importantly, we're getting ever closer to randomized Phase 2 data that we believe will demonstrate much needed benefit in a key population of newly diagnosed metastatic microsatellite-stable colorectal cancer patients. This large group of patients is in desperate need of a therapeutic advance since median overall survival from the time of diagnosis has remained stuck at just around two years.

重要的是，我們越來越接近隨機 2 期數據，我們相信這些數據將在新診斷的轉移性微衛星穩定結直腸癌患者的關鍵人群中證明急需的益處。由於診斷後的中位總存活期仍停留在兩年左右，這一大批患者迫切需要治療進展。

We anticipate sharing mature PFS data as well as additional ctDNA data in the third quarter of this year. The preliminary PFS data we shared recently, accompanied by the supportive ctDNA over time analyses demonstrating early trends in favor of GRANITE immunotherapy, are all very encouraging. And to remind you, these data are following on from and consistent with highly supportive Phase 1/2 data from a single-arm trial in patients with very advanced metastatic disease.

我們預計在今年第三季分享成熟的 PFS 數據以及其他 ctDNA 數據。我們最近分享的初步 PFS 數據，以及隨時間推移的支持性 ctDNA 分析，顯示了有利於 GRANITE 免疫療法的早期趨勢，這些數據都非常令人鼓舞。提醒您的是，這些數據源自於一項針對非常晚期轉移性疾病患者的單臂試驗的高度支持性 1/2 期數據，並與之一致。

We're on the cusp of determinative data from this novel platform in a large patient population that has traditionally been considered unresponsive to immunotherapy. This is a truly exciting prospect for Gritstone, for the fields, and most importantly, for patients and their families.

我們正處於這個新平台在傳統上被認為對免疫療法無反應的大量患者群體中獲得決定性數據的風口浪尖。對於 Gritstone 來說，對於這個領域來說，最重要的是對於患者及其家人來說，這是一個真正令人興奮的前景。

I'd like to thank you all for joining today, and I'll turn the call over to the operator for questions.

我要感謝大家今天加入，我會將電話轉給接線生詢問問題。

(Operator Instructions) Marc Frahm, TD Cowen.

（操作員說明）Marc Frahm，TD Cowen。

Hey. Thanks for taking my questions. Maybe, Andrew, can you speak to how event rates in the CRC trial have evolved since the February update? And given where they are now, just how much uncertainty there still is? Or isn't that the mature PFS data will really be available in Q3?

嘿。感謝您回答我的問題。Andrew，您能否談談自 2 月更新以來 CRC 試驗中的事件發生率有何變化？考慮到他們現在的處境，到底還有多少不確定性？或者說成熟的PFS數據不是要到第三季才能真正出來嗎？

Yeah. It's a little early to give definitive answer because we don't obviously do exhaustive data cuts regularly. That sites find that tiresome. But we have no reason to doubt the maturity of the data at this timepoint because a lot of Phase 3 trials have been run in this very same population with highly consistent data.

是的。現在給出明確的答案還為時過早，因為我們顯然不會定期進行詳盡的數據削減。那些網站覺得很煩。但我們沒有理由懷疑此時數據的成熟度，因為許多 3 期試驗已經在同一人群中進行，數據高度一致。

So the control arm, I strongly expect, will behave as many other control arms have before, with that median PFS of around 11 months. As you're aware from the baseline disease and demographic data that we shared recently, this population of patients is very typical, with 75% having liver metastases. So there's no reason to believe that this is a particularly good or bad population of patients.

因此，我強烈預計該控制臂將像以前的許多其他控制臂一樣運行，中位 PFS 約為 11 個月。正如您從我們最近分享的基線疾病和人口統計中所了解的，這群患者非常典型，其中 75% 患有肝轉移。因此，沒有理由相信這是一個特別好或特別壞的患者群體。

There is, of course, some degree of informative censoring in the way we collect data, meaning that you get data on the patients who progress the fastest. And that is probably working against the GRANITE arm, because most people believe, with good reason, that vaccine immunotherapy is going to be more effective in people with lower volume, less extensive disease. Those patients will progress, on average, a bit more slowly.

當然，我們收集數據的方式存在一定程度的資訊審查，這意味著您可以獲得進展最快的患者的數據。這可能對 GRANITE 團隊不利，因為大多數人有充分理由相信，疫苗免疫療法對於病情較小、疾病範圍較小的人來說會更有效。平均而言，這些患者的進展會稍微緩慢一些。

And of course, that means we have less data in that population, but we have more data in the high-risk group that progress faster, and we showed you those data. And obviously that gave us further reason to be optimistic for mature data in Q3.

當然，這意味著我們在該族群中擁有的數據較少，但我們在高風險群體中擁有更多數據，且進展更快，我們向您展示了這些數據。顯然，這讓我們有進一步的理由對第三季的成熟數據感到樂觀。

Okay, that's helpful. And then maybe on the BARDA front, can you just remind us how that money has actually been allocated? And is it required to be spent on COVID, or is there some risk here that maybe with the avian flu epidemic going on, at least for now on the veterinary side, that some of it may get moved over to flu? And related to that, any work you guys are doing on the avian flu side?

好的，這很有幫助。然後也許在 BARDA 方面，您能否提醒我們這筆錢實際上是如何分配的？是否需要將其用於新冠肺炎治療，或者是否存在一些風險，即隨著禽流感疫情的持續，至少目前在獸醫方面，其中一些可能會轉移到流感上？與此相關，你們在禽流感方面正在做哪些工作？

Yeah. So the specific contract that we were awarded back in the fall of 2023 was part of Project NextGen, which was focused on next-generation COVID vaccines. As you may recall, there were several periods for that contract, and we were in the base period of which that time expired at the end of March. And we are now in a no-cost extension period of that contract while we work out the GMP raw materials for launching the Phase 2b study.

是的。因此，我們在 2023 年秋季獲得的具體合約是 NextGen 計畫的一部分，該計畫專注於下一代新冠疫苗。您可能還記得，合約有幾個時期，我們正處於基期，該時期於 3 月底到期。現在，我們正處於該合約的免費延期期，同時我們正在製定用於啟動 2b 階段研究的 GMP 原料。

So those particular dollars in that particular contract was specific to COVID. You may or may not recall that BARDA has actually shifted those funds into a different funding vehicle called RRPV. So we have applied to that vehicle as well and are now waiting to hear back.

因此，該特定合約中的那些特定美元是專門針對新冠病毒的。您可能記得也可能不記得，BARDA 實際上已將這些資金轉移到名為 RRPV 的不同融資工具。因此，我們也向該車輛提出了申請，現在正在等待回應。

And in regards to your question on flu, Marc, the same principles apply to flu as applied to SARS-CoV-2, which is that, obviously the concern is always that there is ongoing mutation within those surface proteins, particularly the hemagglutinin and the neuraminidase, that can lead to immune evasion. And that means, of course, you're often reacting to what is in the environment around you.

關於你關於流感的問題，馬克，適用於流感的原則與適用於 SARS-CoV-2 的原則相同，也就是說，顯然人們總是擔心這些表面蛋白，特別是血凝素和神經氨酸酶，可導致免疫逃脫。當然，這意味著您經常會對周圍環境做出反應。

The same principles that we deployed against SARS-CoV-2 are relevant here, i.e., that you want durable antibodies and ideally you want T-cell immunity against conserved regions of the virus. Because even if surface proteins are mutating, many of the other nonstructural proteins are not mutating because they're highly constrained, i.e., their function is so critical to the virus that they can't change.

我們針對 SARS-CoV-2 部署的相同原則在這裡也適用，即您需要持久的抗體，並且理想情況下您需要針對病毒保守區域的 T 細胞免疫。因為即使表面蛋白發生突變，許多其他非結構蛋白也不會發生突變，因為它們受到高度限制，即它們的功能對病毒至關重要，因此無法改變。

That's the basic science that underpins our so called chimeric SARS-CoV-2 vaccine, where we include both the surface protein, in the case of SARS-CoV-2, of course, that spike. And we include regions of other non-structural proteins that have conserved epitopes, particularly for CD8 T-cells. You can apply that same logic to flu, and we are doing preclinical work in influenza, as you would imagine.

這就是支撐我們所謂的嵌合 SARS-CoV-2 疫苗的基礎科學，其中我們包括了表面蛋白，對於 SARS-CoV-2，當然是那個尖峰。我們還包括具有保守表位的其他非結構蛋白區域，特別是 CD8 T 細胞。您可以將相同的邏輯應用於流感，正如您想像的那樣，我們正在流感方面進行臨床前工作。

Okay, thank you.

好的謝謝。

Jon Miller, Evercore.

喬恩‧米勒，《Evercore》。

Hi, this is Chengxiang on for Jon. Thanks for taking our question. I guess the first one is for the readout in the second half of the year, what is your bar for success? Do you need to see PFS benefit from patients with low ctDNA at baseline to feel confident moving forward?

大家好，我是喬恩的呈祥。感謝您提出我們的問題。我想第一個是下半年的讀數，你成功的標準是什麼？您是否需要看到基線 ctDNA 較低的患者受益於 PFS，才能對繼續前進充滿信心？

Yeah. The median PFS is 11 months. I think, obviously, we're looking for a meaningful improvement on that, which means a hazard ratio probably better than 0.75. And certainly, the data we've generated so far suggests we're on track to exceed that bar.

是的。中位 PFS 為 11 個月。我認為，顯然，我們正在尋求對此進行有意義的改進，這意味著風險比可能優於 0.75。當然，我們迄今為止產生的數據表明我們有望超越這一目標。

Your question about low ctDNA, there are two populations really that have low ctDNA that we study. There's the group that begins the study with low ctDNA, and that group generally would be called the lower-risk group because we know, and we've shown indeed a few weeks ago, that if you have low ctDNA at baseline, the rate of progression is lower than if you have high ctDNA.

你關於低 ctDNA 的問題，我們研究的兩個人群確實具有低 ctDNA。有一組在開始研究時 ctDNA 較低，該組通常被稱為低風險組，因為我們知道，而且我們幾週前確實已經證明，如果基線 ctDNA 較低，那麼進展速度比 ctDNA 高時要慢。

So that population is a lower-risk population, although they all are expected to progress. So it's not that they have some kind of benign disease. They will progress, and sadly, that disease will kill nearly all of these patients in relatively short order. But they do progress a bit slower, and perhaps vaccine-based immunotherapy will be more effective in that population.

因此，該人群是低風險人群，儘管他們都有望取得進展。所以這並不是說他們患有某種良性疾病。他們會進步，可悲的是，這種疾病將在相對較短的時間內殺死幾乎所有這些患者。但它們的進展確實要慢一些，也許基於疫苗的免疫療法在該族群中會更有效。

There is generally a link between ctDNA level and disease burden. So it is reasonable to assert that the low-ctDNA population have lower disease burden, which is therefore perhaps more amenable to vaccine-based immunotherapy. This is obviously the idea behind the focus on adjuvant indications that Moderna and BioNTech are pursuing. So it is an important population.

ctDNA 水平與疾病負擔之間通常存在關聯。因此，可以合理地斷言低 ctDNA 族群的疾病負擔較低，因此可能更適合基於疫苗的免疫療法。這顯然是 Moderna 和 BioNTech 重點追求的輔助適應症背後的想法。所以說這是一個重要的人群。

Then there's a second group of low ctDNA, which is the patients who complete their induction chemotherapy and then are rendered ctDNA negative by that induction chemo. Now, that's good for those patients. It obviously means they've done well on chemo. Sadly, most of them will recur, however, and that's an analysis that you may recall we presented a few weeks ago.

接著是第二組低 ctDNA，即完成誘導化療後 ctDNA 呈陰性的患者。現在，這對那些病人有好處。這顯然意味著他們在化療方面做得很好。然而，遺憾的是，其中大多數都會再次發生，您可能還記得我們幾週前提出的分析。

And what we were able to show is that although the numbers are obviously quite small, there is a difference in the two arms whereby patients receiving vaccines stay negative for longer than the patients in the control arm. And there is more radiologic progressive disease in the control group than in the vaccine-treated group.

我們能夠證明的是，儘管數字顯然很小，但兩組之間存在差異，接受疫苗的患者比對照組的患者保持陰性的時間更長。對照組的放射學進展性疾病比疫苗治療組多。

So those data are certainly encouraging, and obviously we'll be following up in that population as well. So two different ways to answer your question, but both of them are important. And both of them in principle, could do even better on vaccine than the high risk group where we currently have the most mature PFS data.

因此，這些數據無疑令人鼓舞，顯然我們也會對該族群進行追蹤。有兩種不同的方式來回答你的問題，但都很重要。原則上，他們在疫苗方面的表現可能比我們目前擁有最成熟的 PFS 數據的高風險群體更好。

Thanks so much. Just want to follow up on the ctDNA. I guess, why did ctDNA continue to decrease in the chemo arm after induction therapy? And do you have any thoughts on what sort of ctDNA endpoint might be more predictive for survival?

非常感謝。只是想跟進 ctDNA。我猜，為什麼誘導治療後化療組的 ctDNA 繼續下降？您對哪種 ctDNA 終點可能更能預測存活有什麼想法嗎？

So we don't know. We did not anticipate that. Obviously, we wouldn't have set the endpoint the way we did. So clearly, we had a failure of the endpoint in the study. That's an important distinction that I think has been lost on a lot of people.

所以我們不知道。我們沒有預料到這一點。顯然，我們不會像以前那樣設定端點。很明顯，我們的研究終點失敗了。我認為很多人都忽略了這個重要差異。

You can have an endpoint fail or a product fail, or both. In this case, the endpoint failed because we saw ctDNA dropping in the control group just for the first three to four weeks after the completion of induction chemo. And so that's presumably telling us that there is some delayed or persistent effect of the induction chemotherapy.

您可能會遇到端點故障或產品故障，或兩者兼而有之。在這種情況下，終點失敗了，因為我們看到對照組的 ctDNA 在誘導化療完成後的前三到四週內下降。因此，這可能告訴我們誘導化療有一些延遲或持續的效果。

We had no data to guide us before we designed the study. So this was a new observation, and obviously, it's one that tripped us up. But at some level, not that important, because obviously what matters, A, is that PFS is delivering clear signals here and is a more relevant regulatory endpoint, as we discussed in this call. And secondly, the long-term ctDNA analysis is highly consistent with the PFS signal. In other words, patients on vaccine do better. ctDNA is controlled for longer, and that certainly is what you would expect from an active therapy in this disease setting.

在設計這項研究之前，我們沒有數據來指導我們。所以這是一個新的觀察，顯然，這是一個讓我們絆倒的觀察。但在某種程度上，這並不重要，因為顯然重要的是，A，PFS 在這裡傳遞了明確的信號，並且是一個更相關的監管終點，正如我們在本次電話會議中討論的那樣。其次，長期 ctDNA 分析與 PFS 訊號高度一致。換句話說，接種疫苗的患者表現較好。 ctDNA 的控制時間更長，這當然是您對這種疾病的積極治療所期望的。

Now, moving forward in this disease, we will not be worried about ctDNA because we're now potentially entering Phase 3 and we'll be using traditional endpoints, PFS or OS. And obviously, that's something we'll be discussing with the agency at the end of Phase 2 meeting. And as you know, PFS has been used for approval in this first-line disease setting. So that's what we'll be doing in metastatic colorectal cancer.

現在，在這種疾病的治療中，我們不會擔心 ctDNA，因為我們現在可能進入第 3 階段，我們將使用傳統的終點、PFS 或 OS。顯然，這是我們將在第二階段會議結束時與該機構討論的問題。如您所知，PFS 已獲得批准用於第一線疾病治療。這就是我們在轉移性大腸直腸癌方面要做的事情。

However, we obviously, if all goes well, will be developing the program in other settings. And particularly in earlier-stage trials, especially if single arm, ctDNA outcomes are potentially very important as an early efficacy metric before you get to big, randomized studies. And therefore, it is important that we understand how to interrogate ctDNA in a way that renders it a useful surrogate for clinical endpoints such as PFS and OS.

然而，如果一切順利，我們顯然將在其他環境中開發該程式。尤其是在早期試驗中，尤其是單組試驗中，在進行大型隨機研究之前，ctDNA 結果作為早期療效指標可能非常重要。因此，我們必須了解如何以某種方式詢問 ctDNA，使其成為 PFS 和 OS 等臨床終點的有用替代品。

Today, I can't give you the answer because we don't have the mature PFS and OS data, but of course, the data we're generating will be an invaluable resource to enable us to figure out a way to use ctDNA that adeptly captures long-term clinical benefit and can then be deployed in single arm smaller trials in other indications.

今天，我無法給你答案，因為我們沒有成熟的 PFS 和 OS 數據，但當然，我們正在產生的數據將是寶貴的資源，使我們能夠找到一種使用 ctDNA 的方法，巧妙地捕捉長期臨床效益，然後可以部署在其他適應症的單臂小型試驗中。

All right. Thank you so much.

好的。太感謝了。

Thank you.

謝謝。

Mayank Mamtani, B. Riley Securities.

Mayank Mamtani，B. Riley 證券。

Hey, guys. Madison here on for Mayank. Thanks for taking our question. So wondering what do you guys anticipate the touch points will be with the FDA whenever you meet to discuss Phase 3? And also, curious how those patients could look relative to what we've seen in GRANITE after 75% of liver met 50% KRAS, if that's just kind of representative of the population.

大家好。麥迪遜代表 Mayank 出場。感謝您提出我們的問題。那麼想知道每當你們開會討論第三階段時，你們預期 FDA 的接觸點是什麼？而且，我很好奇，在 75% 的肝臟遇到 50% KRAS 後，這些患者與我們在 GRANITE 中看到的情況相比會是什麼樣子，如果這只是人群的代表的話。

And then lastly, the fact we didn't see any pseudo progression, do you expect that would hold in a Phase 3, or is that something that you'll attempt to address in the design in the event there is pseudo progression? Appreciate it, guys. Thanks.

最後，我們沒有看到任何偽進展，您是否期望在第三階段中保持這一點，或者如果存在偽進展，您是否會在設計中嘗試解決這個問題？非常感謝，夥計們。謝謝。

Yeah. Thanks, Madison. Good question. So in a slightly different order, in which you ask the questions, by design, this was a very straightforward frontline study across the United States in a variety of centers with very straightforward inclusion and exclusion criteria, very standard.

是的。謝謝，麥迪遜。好問題。因此，按照略有不同的順序，按照設計，您提出問題的順序是一項非常簡單的前沿研究，在美國各地的各個中心進行，具有非常簡單的納入和排除標準，非常標準。

And that's good, of course, because it means there's not much opportunity for patient selection. You're just taking the patients that come through the door. And there aren't that many trials in frontline colorectal cancer. So most people who were clinical trial eligible and at a site where our trial was operating would have been offered our study, which is why it enrolled very swiftly, particularly in the first half of 2023.

當然，這很好，因為這意味著選擇患者的機會不多。你只是帶走進門的病人。而且針對第一線大腸直腸癌的試驗並不多。因此，大多數符合臨床試驗資格並且在我們的試驗進行地點的人都會獲得我們的研究機會，這就是為什麼它能非常迅速地入組，特別是在 2023 年上半年。

So there is unmet need there. The trial is very straightforward and recruits patients without any special selection. We don't anticipate changing that for Phase 3. Why would you if you want a representative population? So that's good news.

所以那裡存在著未被滿足的需求。這項試驗非常簡單，招募患者時沒有經過任何特殊選擇。我們預計第三階段不會改變這一點。如果你想要有代表性的人口，為什麼要這麼做？這是個好消息。

And obviously, we would anticipate that the degree of liver metastases and KRAS mutations will be constant in the Phase 3 because, of course, your dream is to run a Phase 3 that is basically unchanged from your Phase 2. That reduces the chance that something new, you've made some new assumption or something else is happening that's altering the outcome. You want that so called sleep-easy Phase 3.

顯然，我們預期肝轉移和 KRAS 突變的程度在第 3 階段將保持不變，因為當然，您的夢想是進行與第 2 階段基本相同的第 3 階段。這減少了新的事情、你所做的新假設或其他事情正在發生而改變結果的可能性。你想要所謂的輕鬆睡眠第三階段。

So our incentive is to change as little as possible. And obviously, we'll go to the FDA. And the traditional forum is an end of Phase 2 meeting, which we'd anticipate towards the end of this year, taking to them the data from this study, which, of course, we'll have in hand in Q3. And then we'll be discussing, among other things, the Phase 3 primary efficacy endpoint. And that is likely to be a choice between PFS and OS.

所以我們的動機是盡量少改變。顯然，我們會去 FDA。傳統的論壇是第二階段會議的結束，我們預計在今年年底舉行，並向他們提供這項研究的數據，當然，我們將在第三季收到這些數據。然後我們將討論第 3 期主要療效終點等。這很可能是 PFS 和 OS 之間的選擇。

We also, of course, need to align with the FDA on manufacturing because these are complex products. We've obviously been in lockstep with the FDA from the very get go. In fact, we first spoke to the FDA about manufacturing before we were in the clinic when we were literally designing the layout of our biomanufacturing facility. So we held a Type-C meeting back then just to solicit FDA's input to make sure that we were on the right track in terms of the way we make these products.

當然，我們還需要在製造方面與 FDA 保持一致，因為這些是複雜的產品。顯然，我們從一開始就與 FDA 保持同步。事實上，在我們進入診所之前，當我們真正設計我們的生物製造設施的佈局時，我們首先與 FDA 討論了製造問題。因此，我們當時召開了 Type-C 會議，只是為了徵求 FDA 的意見，以確保我們在製造這些產品的方式方面走在正確的軌道上。

There's obviously a step up in regulatory quality as you move to Phase 3 and commercial, and we need to make sure that we're aligned with the agency. That's also part of the end of Phase 2 meeting alongside the clinical endpoint discussions.

隨著進入第三階段和商業化，監管品質顯然會提高，我們需要確保我們與該機構保持一致。這也是第二階段會議結束以及臨床終點討論的一部分。

Got it. Thank you.

知道了。謝謝。

Kaveri Pohlman, BTIG.

卡維裡·波爾曼，BTIG。

Hi, this is Christian. I'm on for Kaveri today. My first question is, I would like an update on the CORAL program. I saw that you guys presented positive data recently on the CORAL study on South African patients, and there was positive data in the three-vaccine candidates. So is there any development there? Are you guys planning to -- which candidate are you guys planning to move forward?

嗨，這是基督徒。今天我要去卡維裡。我的第一個問題是，我想了解 CORAL 計劃的最新情況。我看到你們最近提出了關於南非患者的 CORAL 研究的積極數據，並且三種候選疫苗也有積極的數據。那麼那裡有發展嗎？你們打算──你們打算提名哪位候選人？

Obviously, if successful with our BARDA study, we'll be moving forward another candidate because, of course, we're expecting there to be an update of the strain that is required for the fall season of 2024. As you're aware, WHO and the EU have issued guidance to use the JN.1 variant. If you remember, obviously, last year, it was the XBB.1.5 variant. So there will be a strain change.

顯然，如果我們的 BARDA 研究取得成功，我們將推進另一個候選者，因為當然，我們預計 2024 年秋季所需的壓力將會有更新。如您所知，世界衛生組織和歐盟已發布了使用 JN.1 變體的指南。如果你還記得的話，顯然是去年的 XBB.1.5 變體。所以會出現應變變化。

We've not disclosed the exact nature of the T-cell component that we'll include in the vaccine, but that will be included. That's part of our chimeric vaccine design intended to induce protective antibodies as well as those protective T-cell responses against conserved antigens. So that's the expectation going forward, and that's the primary focus of the CORAL program right now.

我們尚未透露疫苗中包含的 T 細胞成分的確切性質，但我們會包含在內。這是我們嵌合疫苗設計的一部分，旨在誘導保護性抗體以及針對保守抗原的保護性 T 細胞反應。這就是未來的期望，也是 CORAL 計劃目前的主要關注點。

Okay, thank you. And regarding the BARDA study, I just noticed in the press release that the company will be initiating that as soon as they can. Should we still expect that in fall 2024 or is that being reevaluated?

好的謝謝。關於 BARDA 研究，我剛剛在新聞稿中註意到該公司將盡快啟動這項研究。我們是否仍應預期 2024 年秋季會出現這種情況，還是正在重新評估？

Yeah. It depends a little on our ability to meet the FDA's criteria around GMP raw materials. So obviously, that's a little contingent on further interactions with the agency, which is why we are cautious about specific guidance at this point.

是的。這在一定程度上取決於我們是否有能力滿足 FDA 關於 GMP 原料的標準。顯然，這在一定程度上取決於與該機構的進一步互動，這就是為什麼我們目前對具體指導持謹慎態度。

Okay. Thank you so much.

好的。太感謝了。

Thank you.

謝謝。

Catherine Novack, JonesTrading.

凱瑟琳·諾瓦克，瓊斯交易公司。

Oh, hi, guys. Good afternoon. Thanks for taking the question. Just a couple, I guess. I wanted to ask about the prevalence of high-risk disease versus low risk. And do you consider this a predictive enrichment factor or mainly saw benefit due to the fact that patients had more mature PFS curves?

哦，嗨，夥計們。午安.感謝您提出問題。我猜只是一對。我想詢問高風險疾病與低風險疾病的盛行率。您是否認為這是一個預測豐富因素，或者主要是因為患者擁有更成熟的 PFS 曲線而受益？

Yeah. Thanks, Catherine. So the way we did this analysis was to look at the -- we calculated the baseline circulating tumor DNA on every subject where we had that information. And then we took the control group and we split it right down the middle, and we just bifurcated that population. We then applied that same cutoff to the vaccine arm, the test arm, and it actually was slightly lower than the median for the vaccine arm.

是的。謝謝，凱瑟琳。因此，我們進行分析的方式是查看——我們計算了我們掌握該資訊的每個受試者的基線循環腫瘤 DNA。然後我們把對照組從中間一分為二，然後我們就把這個群體分成兩個部分。然後，我們將相同的臨界值應用於疫苗組、測試組，它實際上略低於疫苗組的中位數。

So the vaccine patients actually had slightly higher baseline ctDNA than the control arm, which obviously works against the vaccine arm, all things being equal, which is good from a conservative data analysis point of view. So that's how we set it. So it was a 50-50 in the control arm, slightly more in the vaccine arm.

因此，疫苗患者的 ctDNA 基線實際上比對照組略高，這顯然對疫苗組不利，在所有條件相同的情況下，從保守的數據分析角度來看，這是件好事。我們就是這樣設定的。因此，對照組的比例是 50-50，疫苗組的比例略高一些。

The reason we did that was simply to try and generate a more mature data set, because of course, everybody is asking the question, ourselves included, what will these data look like when we have the mature data? And so what we were trying to do was find a very fair way of identifying a population of patients who have events faster. And baseline ctDNA is remarkably efficient at selecting for the patients who have faster events. And that's clear from the Kaplan-Meier curves that we showed. So that's why we did it.

我們這樣做的原因只是為了嘗試產生一個更成熟的資料集，因為當然，每個人都在問這個問題，包括我們自己，當我們擁有成熟的資料時，這些資料會是什麼樣子？因此，我們試圖做的是找到一種非常公平的方法來更快地識別出發生事件的患者群體。基線 ctDNA 在選擇事件較快的患者方面非常有效。從我們展示的卡普蘭-邁耶曲線中可以清楚地看出這一點。這就是我們這樣做的原因。

And you could argue reasonably, that the high-risk population is the population that's going to do the worst on vaccine, because as I mentioned in my response to another question, there is a general belief, based now on data, that lower volume disease does better on immunotherapy, and perhaps particularly on vaccine immunotherapy. The lowest volume disease is in the adjuvant setting. And that's where, of course, we've seen particular success by Moderna, who obviously did not see signal in advanced metastatic disease but have seen signal in high-risk adjuvant melanoma.

你可以合理地爭辯說，高風險人群是在疫苗方面表現最差的人群，因為正如我在回答另一個問題時提到的那樣，根據現在的數據，人們普遍認為疾病數量較少在免疫療法方面表現更好，也許尤其是在疫苗免疫療法方面。最低體積的疾病發生在輔助治療。當然，這就是我們看到 Moderna 特別成功的地方，他顯然沒有在晚期轉移性疾病中看到訊號，但在高風險輔助黑色素瘤中看到了訊號。

So within a metastatic colorectal population, there are obviously some patients with very extensive disease and some patients with very mild or minor disease, but they all have metastatic colorectal cancer. ctDNA splits them and it gives you more data faster in that high-risk group with more extensive disease. So the fact we saw such a strong signal there is reassuring that as the data mature, we will then see a signal at least as strong in the low-risk group may be stronger.

因此，在轉移性大腸直腸癌人群中，顯然有一些患者患有非常廣泛的疾病，也有一些患者患有非常輕微或輕微的疾病，但他們都患有轉移性結直腸癌。 ctDNA 將它們分開，可以更快地為您提供更多患有更廣泛疾病的高風險群體的數據。因此，我們看到如此強烈的訊號這一事實令人放心，隨著數據的成熟，我們將看到低風險群體中至少同樣強烈的訊號可能會更強。

And therefore, our intention is not to think about this high-risk stratification once we're past Q3. And at that point, we anticipate we'll be including everybody and treating everybody, and hopefully seeking a label in everybody. Because in principle, if the product works in everybody, which is what we anticipate, then of course, you don't want to be selecting out against particular patients.

因此，我們的目的是在第三季過後不再考慮這種高風險分層。到那時，我們預計我們將包括每個人並對待每個人，並希望在每個人身上找到一個標籤。因為原則上，如果該產品對每個人都有效，這是我們所期望的，那麼您當然不希望針對特定患者進行選擇。

Got it. Thank you. That's very helpful.

知道了。謝謝。這非常有幫助。

Yeah.

是的。

Roy Buchanan, Citizens JMP.

羅伊·布坎南，公民 JMP。

Hey, thanks for taking my questions. I think you've just answered my GRANITE question, which is stratifying by ctDNA. So it sounds like you're not going to do that going forward into the Phase 3.

嘿，謝謝你回答我的問題。我想您剛剛回答了我的 GRANITE 問題，該問題是透過 ctDNA 進行分層的。所以聽起來你不會在進入第三階段時這樣做。

Well, let's be clear, Roy. We haven't got the data yet in the low-risk group. So everything we're saying today is speculation. What we have got is data in the high-risk group, which looks very good. Now we wait for data in the low-risk group.

好吧，讓我們說清楚，羅伊。我們還沒有得到低風險組的數據。所以我們今天所說的一切都是猜測。我們得到的是高風險組的數據，看起來非常好。現在我們等待低風險組的數據。

So I want to be super clear about this. It's not that we have no signal in the low-risk group. We have no data in the low-risk group, because very few of them, as of early March, had achieved a progression or death event.

所以我想非常清楚這一點。並不是說我們在低風險族群中沒有訊號。我們沒有低風險組的數據，因為截至 3 月初，他們中很少有人出現進展或死亡事件。

So it's not evidence of absence of effect; its absence of any evidence about anything, and therefore you just wait. But what you would expect, based on the literature and what we've seen from others, is that the effect of the vaccine in that low-risk group will be at least as good as in the high-risk group, perhaps better. And if that's indeed what we see, then there would be no reason to worry about patient selection going forward.

所以這並不是沒有效果的證據，而是沒有效果的證據。沒有任何證據表明任何事情，因此你只需等待。但根據文獻和我們從其他人那裡看到的情況，你會期望疫苗在低風險族群中的效果至少與高風險族群一樣好，甚至可能更好。如果這確實是我們所看到的，那麼就沒有理由擔心未來的患者選擇。

Okay, got it. Okay, thank you. I guess a few on CORAL. So this RRPV holding vehicle or whatever it is, and you're waiting to hear back from that. Do you have any sense on when you might hear back on that? And is that a new set of people that are going to decide whether they like this program or that program or technology versus the first decision on the GRANITE?

好，知道了。好的謝謝。我猜有一些是在 CORAL 上的。所以這個 RRPV 持有車輛或其他東西，你正在等待回應。您知道什麼時候可以收到回覆嗎？是一群新的人將決定他們是否喜歡這個專案或那個專案或技術，而不是 GRANITE 上的第一個決定？

It is a different entity, but obviously there is relatedness. But the exact nature of those relationships is not very apparent to outsiders like us. So related, but distinct.

這是一個不同的實體，但顯然存在相關性。但這些關係的確切性質對於我們這樣的局外人來說並不是很明顯。如此相關，卻又截然不同。

Okay. Okay, great.

好的。好的，太好了。

It is a consortium that's under BARDA's direction.

這是一個在 BARDA 指導下的財團。

And do you have any timelines of when they're going to get back to you?

您有他們何時回覆您的時間表嗎？

We have not provided any guidance on that.

我們尚未就此提供任何指導。

Okay. And then you mentioned potentially partnering to fund the ID programs. Will that also potentially include COVID-19? Thanks.

好的。然後您提到了可能合作資助 ID 項目。這也可能包括 COVID-19 嗎？謝謝。

Yes, potentially.

是的，有可能。

Okay, thank you.

好的謝謝。

Thanks, Roy.

謝謝，羅伊。

Arthur He, H.C. Wainwright.

何亞瑟，H.C.溫賴特。

Hey, good afternoon, Andrew and team. This is Arthur on for [Shah]. I just had a quick one regarding the GRANITE. Just curious, when you see the ctDNA reduction opposed to the chemo, did you see -- is there any correlation for the reduction with the baseline character of the tumor? I'm just curious, is there any way you guys could minimize these noisy background if you go into use a ctDNA to further as a biomarker for the evaluation in the future?

嘿，下午好，安德魯和團隊。這是亞瑟在為[沙阿]。我剛剛快速了解了花崗岩。只是好奇，當您看到與化療相反的 ctDNA 減少時，您是否看到 - 這種減少與腫瘤的基線特徵有任何相關性嗎？我只是很好奇，如果你們將來使用 ctDNA 進一步作為評估的生物標記物，有什麼方法可以最大限度地減少這些噪音背景嗎？

We haven't performed those analyses yet. Obviously, it's a phenomenon that relates to the tumor response to chemotherapy, specifically to FOLFOX/FOLFIRI plus bevacizumab. And that regimen is only used in colorectal cancer. Derivatives of it, I guess, used in pancreatic cancer, but it wouldn't have great utility outside of this colorectal cancer setting. And so determining who does well on chemotherapy is obviously not particularly critical to our development program going forward.

我們還沒有進行這些分析。顯然，這種現象與腫瘤對化療的反應有關，特別是 FOLFOX/FOLFIRI 加貝伐單抗的反應。此療法僅用於大腸直腸癌。我猜它的衍生物用於治療胰臟癌，但在結直腸癌之外它不會有很大的用處。因此，確定誰在化療中表現良好顯然對我們未來的發展計畫並不是特別重要。

All right. Thanks. And my second question for the update, further readout in the third quarter, besides the PFS -- mature PFS and more ctDNA data, what other data set could we expect can give us more information regarding the pivotal study design?

好的。謝謝。我的第二個問題是更新，第三季的進一步讀數，除了PFS——成熟的PFS 和更多ctDNA 數據之外，我們還可以期待哪些其他數據集可以為我們提供有關關鍵研究設計的更多資訊?

Yeah. So the overall survival data will still be very immature at that point, median overall survival is around two years in this disease. So again, following the same logic, if PFS is basically around one year or just shy, you need to give it another year to get to very mature OS data.

是的。因此，到那時總存活數據仍非常不成熟，這種疾病的中位總存活期約為兩年。因此，同樣，遵循相同的邏輯，如果 PFS 基本上約為一年或只是較短，則需要再給它一年才能獲得非常成熟的作業系統資料。

Now we are doing some additional analyses. Karin, our Head of R&D is on the phone here. So, Karin, perhaps you want to give a little flavor as to what additional correlates we might have for the Q3 update.

現在我們正在做一些額外的分析。我們的研發主管 Karin 正在打電話。所以，Karin，也許您想稍微介紹一下我們在第三季更新中可能有哪些額外的相關內容。

Yeah. We are looking in a subset of the patient population. We perform TCR-Seq, we perform [A.L.I.C.E] bot analysis. So we do look at translational data, which we actually have published significant data in our Nature Medicine papers. So we do some of that work, but we don't anticipate the data to look any different to our goal for manuscript.

是的。我們正在尋找一部分患者群體。我們執行 TCR-Seq，我們執行 [A.L.I.C.E] 機器人分析。因此，我們確實研究了轉化數據，實際上我們已經在《自然醫學》論文中發表了重要數據。因此，我們做了一些工作，但我們預計這些數據與我們的手稿目標不會有任何不同。

But TCR-Seq an A.L.I.C.E bot, you can anticipate that. We are also -- potentially, if we have enough cells perform ICS, looking for fully functionality or even killing, so we have a great toolbox. And depending on the number of cells we have from these blood trials, we will, in a subset only of these patients, looking for T-cell response, TCR-Seq, as well as functionality of the T-cells.

但 TCR-Seq 是一個 A.L.I.C.E 機器人，這一點你可以預料到。如果我們有足夠的細胞執行 ICS，我們也有可能尋找完整的功能甚至殺死，所以我們有一個很棒的工具箱。根據我們從這些血液試驗中獲得的細胞數量，我們將只在這些患者的子集中尋找 T 細胞反應、TCR-Seq 以及 T 細胞的功能。

Great. Thanks for the addition of color. Thanks for taking my question.

偉大的。感謝您添加顏色。感謝您提出我的問題。

Thank you.

謝謝。

Corinne Johnson, Goldman Sachs.

科琳·約翰遜，高盛。

Hi, this is Omari on for Corinne. I have a couple questions. What gives you confidence that the PFS will strengthen as the data matures? And on the hazard ratio, is the piecewise Cox pH model a prespecified analysis?

大家好，我是科琳娜的奧馬裡。我有幾個問題。是什麼讓您相信 PFS 將隨著資料的成熟而增強？關於風險比，分段 Cox pH 模型是預先指定的分析嗎？

So the confidence comes from two primary sources, directly and one indirect source. First of all, we saw the same phenomenon of PFS and OS extension in the Phase 1/2 study in third-line colorectal cancer patients. Not a randomized study, but those who had reductions in their bone biomarkers, including ctDNA, had this apparently extended PFS and OS. So we're repeating that observation in this study.

因此，信心來自兩個主要來源，一個是直接來源，一個是間接來源。首先，我們在第三線大腸直腸癌患者的 1/2 期研究中看到了同樣的 PFS 和 OS 延長的現象。這不是一項隨機研究，但那些骨生物標記（包括 ctDNA）減少的患者的 PFS 和 OS 明顯延長。因此，我們在這項研究中重複了這個觀察結果。

Secondly, the high-risk analysis gives you a way of peering into the future, and it's obviously not a perfect analysis. No one can foretell the future. If they could, it would be easy. But it's a reasonable way of asking the question, if I expect the low-risk group to behave similar to the high-risk group, then what would I see in the future? And obviously, the high-risk analysis is quite mature and looked very encouraging. So that's the second direct bit of evidence to encourage optimism for the Q3 mature data.

其次，高風險分析為你提供了一種展望未來的方法，但這顯然不是一個完美的分析。沒有人能夠預測未來。如果他們可以的話，那就很容易了。但這是一個合理的提問方式，如果我期望低風險群體的行為與高風險群體相似，那麼我將來會看到什麼？顯然，高風險分析已經相當成熟，看起來非常令人鼓舞。這是鼓勵人們對第三季成熟數據持樂觀態度的第二個直接證據。

The indirect support comes from the notion that the data we're waiting for are in the low-risk patients. And data from other players, most notably Moderna, suggests that those low-volume disease patients are the ones that do best on vaccine-based immunotherapy. Therefore, if you believe that that applies to this study, we should see signals at least as strong, if not stronger, in the lower-risk population as the dataset rounds out and matures.

間接支持來自這樣的觀念：我們正在等待的數據來自低風險患者。其他參與者（尤其是 Moderna）的數據表明，那些低量疾病患者是在基於疫苗的免疫療法中效果最好的患者。因此，如果您認為這適用於本研究，那麼隨著資料集的完善和成熟，我們應該在低風險族群中看到至少同樣強烈（如果不是更強）的訊號。

Your second question was about the GPW statistical test, and I couldn't quite catch it. Was the question, are we using that in the summer in Q3?

你的第二個問題是關於GPW統計測試的，我不太明白。問題是，我們會在第三季的夏天使用它嗎？

Piecewise Cox pH model, was that a pre-specified analysis of this study?

分段 Cox pH 模型，這是本研究的預先指定的分析嗎？

Yes. So we've actually been in a lengthy dialog with FDA around the way to statistically analyze the study because it is clear that patients are randomized at the beginning of their induction chemotherapy, and for the first, on average, five months, the treatments are identical across the two arms of the study. And then the treatments diverge, and therefore, the Kaplan-Meier plots of progression-free survival will not meet the proportional hazards assumption. And that is a requirement if you're going to use the standard log-rank test.

是的。因此，我們實際上已經與 FDA 圍繞統計分析該研究的方式進行了長時間的對話，因為很明顯，患者在誘導化療開始時是隨機的，並且在最初的平均五個月裡，治療是研究的兩個分支是相同的。然後治療方法會出現分歧，因此，無惡化存活期的 Kaplan-Meier 圖將不符合比例風險假設。如果您要使用標準對數秩測試，這是一個要求。

So we knew that the way the study was designed, log rank was not the appropriate statistical test and appropriate way to analyze these curves that. In fact, what you wanted to do was a time-weighted system. So we entered this discussion with the agency and we settled with them on GPW, the global -- sorry, generalized piecewise analysis.

所以我們知道研究的設計方式，對數排序並不是適當的統計檢定和分析這些曲線的適當方法。事實上，你想做的是一個時間加權系統。因此，我們與該機構進行了討論，並與他們就 GPW 達成一致，即全球——抱歉，廣義分段分析。

And we've done a very simple model for this study. Any progression event prior to six months is given a weighting of 0, and any progression event after six months is given a weighting of 1. That's the way we've analyzed these data, and that was pre-specified, yes.

我們為這項研究做了一個非常簡單的模型。六個月之前的任何進展事件的權重為 0，六個月後的任何進展事件的權重為 1。這就是我們分析這些數據的方式，這是預先指定的，是的。

Thank you.

謝謝。

Thank you.

謝謝。

Thank you. At this time, there are no further questions in queue. I'd like to turn the call back to Andrew Allen for closing comments.

謝謝。目前，隊列中沒有其他問題。我想將電話轉回安德魯艾倫以徵求結束意見。

Thank you very much. That represents the end of our call. So we have nothing further to add. Just like to thank you for your time and attention. Obviously, we're very excited to see these data in Q3, and we hope to be able to really move the ball forward for these patients who've been waiting a long time, for some reasons, for optimism. And with that, thank you very much.

非常感謝。這代表我們的通話結束。所以我們沒有什麼好補充的。只是想感謝您的時間和關注。顯然，我們非常高興在第三季度看到這些數據，我們希望能夠真正為這些因某些原因等待了很長時間的患者帶來樂觀情緒。非常感謝。

Thank you. This does conclude today's teleconference. You may disconnect your lines at this time. Thank you for your participation and have a great day.

謝謝。今天的電話會議到此結束。此時您可以斷開線路。感謝您的參與，祝您有美好的一天。