莫德納 (MRNA) 2018 Q4 法說會逐字稿

Good morning, and welcome to the Moderna Corporate Update and 2018 Financial Review Conference Call. (Operator Instructions) Please be advised that the call is being recorded.

早上好，歡迎來到 Moderna 公司更新和 2018 年財務審查電話會議。 （操作員說明）請注意，通話正在錄音中。

At this time, I would like to turn the call over to Laura Schneck, Investor Relations at Moderna. Please proceed.

在這個時候，我想把電話轉給 Moderna 投資者關係部的 Laura Schneck。請繼續。

Thank you, operator. Good morning, and welcome to the Moderna Corporate Update and 2018 Financial Review Conference Call.

謝謝你，運營商。早上好，歡迎來到 Moderna 公司更新和 2018 年財務審查電話會議。

This morning, we issued a press release that outlines the topics of events discussed today. You can access the press release as well as the slides that we'll be reviewing by going to the Investors section of our website at modernatx.com.

今天上午，我們發布了一份新聞稿，概述了今天討論的事件主題。您可以訪問我們網站 modernatx.com 的“投資者”部分，訪問我們將要審查的新聞稿和幻燈片。

Today, on this conference call, we have Stéphane Bancel, our Chief Executive Officer; Tal Zaks, our Chief Medical Officer; and Lorence Kim, our Chief Financial Officer. Stephen Hoge, our President, will also join us when we open up for Q&A at the end.

今天，在這次電話會議上，我們的首席執行官 Stéphane Bancel 出席了會議；我們的首席醫療官 Tal Zaks；和我們的首席財務官 Lorence Kim。我們的總裁 Stephen Hoge 也將在我們最後開放問答時加入我們。

Before we begin, I would like to remind everyone that this conference call will include forward-looking statements. Slide 2 of the accompanying presentation and our SEC filings have important risk factors that could cause our actual performance and results to differ materially from those expressed or implied in these forward-looking statements. We undertake no obligation to update or revise the information provided on this call as a result of new information or future results and developments.

在我們開始之前，我想提醒大家，本次電話會議將包含前瞻性陳述。隨附演示文稿的幻燈片 2 和我們提交給美國證券交易委員會的文件具有重要的風險因素，可能導致我們的實際業績和結果與這些前瞻性陳述中明示或暗示的業績和結果存在重大差異。我們不承擔因新信息或未來結果和發展而更新或修改本次電話會議上提供的信息的義務。

I will now pass the call over to Stéphane.

我現在將電話轉給 Stéphane。

Thank you, Laura, and good morning, everyone. Welcome to Moderna's first quarterly conference call as a public company.

謝謝勞拉，大家早上好。歡迎來到 Moderna 作為上市公司的首次季度電話會議。

As you know, we believe at Moderna, that mRNA has a potential to become a new class of medicines. And since Moderna's inceptions, we have worked hard to build the company that could become the leader in the field. What that drives in us is a potential to make new medicines for untreated diseases, medicines which cannot technologically be made using small or large molecules.

如您所知，在 Moderna，我們相信 mRNA 有可能成為一類新的藥物。自 Moderna 成立以來，我們一直致力於打造成為該領域領導者的公司。驅動我們的是為未治療的疾病製造新藥的潛力，這些藥物在技術上無法使用小分子或大分子製造。

We believe that, over time, this can go beyond our current strategic areas of infectious disease: oncology, rare genetic diseases and cardiovascular diseases. Because mRNA is an information-containing molecule, we believe that this new class of medicines and the company we have built around it may have many advantages. First, we are able to use similar technology components across programs. As a result and over time, as we derisk the use of those components, successive mRNA medicines should have a higher probability of technical success than traditional medicines.

我們相信，隨著時間的推移，這可能會超越我們目前的傳染病戰略領域：腫瘤學、罕見遺傳病和心血管疾病。因為 mRNA 是一種包含信息的分子，我們相信這種新型藥物和我們圍繞它建立的公司可能有很多優勢。首先，我們能夠跨程序使用類似的技術組件。因此，隨著時間的推移，隨著我們降低使用這些成分的風險，連續的 mRNA 藥物應該比傳統藥物具有更高的技術成功概率。

Second, by investing in automation, robotics and IT, we should be able to move very quickly on our small molecule or large molecule technologies. Every time we make a product at every scale, we intend to use similar manufacturing processes, accelerating time lines for both the discovery of new development candidate as well as the scale-up for clinical trials. And finally, because we make mRNA in a liquid-phase sulfur solution, we believe that over time, our costs of -- would be similar to small molecule injectable commercial products. With the possibility to build the new class of medicines while helping many patients and creating value for our shareholders along the way, we focus on managing 4 different type of risks: technology risk, biology risk, exception risk, financing risk.

其次，通過投資自動化、機器人技術和 IT，我們應該能夠在我們的小分子或大分子技術上快速發展。每次我們生產各種規模的產品時，我們都打算使用類似的製造工藝，從而加快發現新開發候選產品以及擴大臨床試驗規模的時間線。最後，因為我們在液相硫溶液中製造 mRNA，我們相信隨著時間的推移，我們的成本將與小分子可注射商業產品相似。為了有可能在幫助許多患者的同時為我們的股東創造價值的同時打造新型藥物，我們專注於管理 4 種不同類型的風險：技術風險、生物學風險、異常風險、融資風險。

As you can see on Slide 4, it has always been our goal to derisk each of our modalities by beginning with a development candidate that could allow us to systematically and separately address the biology risk and the technology risk. Early on, we determined that vaccines presented the least technology risk and, therefore, decided to pursue this modality first.

正如您在幻燈片 4 中看到的那樣，我們的目標一直是通過開發候選藥物來降低我們每一種模式的風險，這可以讓我們系統地、單獨地解決生物學風險和技術風險。早些時候，我們確定疫苗的技術風險最小，因此決定首先採用這種方式。

From a biology risk perspective, we started with influenza vaccine to see if we could safely demonstrate in the Phase I trial a defined level of antibodies in healthy volunteers not previously exposed to the virus. At the time of our IPO, we had advanced programs across 3 of our modalities in the clinic: cancer vaccines, intratumoral immuno-oncology and localized regenerative therapeutics.

從生物學風險的角度來看，我們從流感疫苗開始，看看我們是否可以在 I 期試驗中安全地證明以前未接觸過該病毒的健康志願者體內的抗體水平達到規定水平。在我們首次公開募股時，我們在臨床上有 3 種模式的先進項目：癌症疫苗、腫瘤內免疫腫瘤學和局部再生療法。

Already in 2019, we have initiated human dosing in our fifth modality, systemic secreted therapeutics with mRNA-1944, an mRNA encoding antibody against the Chikungunya virus. This program uses the same delivery technology as the 4 rare genetic disease programs: MMA, PA, PKU and Fabry as well as our Relaxin cardiology program.

早在 2019 年，我們就已經開始以我們的第五種方式進行人體給藥，即使用 mRNA-1944 的全身分泌療法，這是一種針對基孔肯雅病毒的 mRNA 編碼抗體。該計劃使用與 4 種罕見遺傳病計劃相同的交付技術：MMA、PA、PKU 和 Fabry 以及我們的 Relaxin 心髒病學計劃。

On Slide 5, you can see our 2019-2020 priorities. As we build the company, our top priority is to advance our development pipeline to get these important innovative medicines to patients. We're also focused on growth. And therefore, other subsets of our team focus on creating new development candidates within our existing 6 modalities. Given that these new development candidates use the same technology component that's also already in the clinic, we're able to significantly reduce technology risk and move swiftly from a drug concept to a development candidate. Our further real focus is on the long term, meaning inventing new modalities, which can deliver mRNAs to new tissues and/or cell types.

在幻燈片 5 上，您可以看到我們 2019-2020 年的優先事項。在我們建立公司的過程中，我們的首要任務是推進我們的開發管道，為患者提供這些重要的創新藥物。我們也專注於增長。因此，我們團隊的其他子集專注於在我們現有的 6 種模式中創建新的開發候選人。鑑於這些新開發候選藥物使用的技術組件與臨床中已有的相同，我們能夠顯著降低技術風險，並迅速從藥物概念轉變為開發候選藥物。我們進一步真正關注的是長期，這意味著發明新的方式，可以將 mRNA 輸送到新的組織和/或細胞類型。

On Slide 6, outlined in red, you can see our pipeline has advanced in the 90 days since our IPO. Let me spend a minute on this from right to left. We are planning a Phase II study for PCV and the Phase II trial for OX40L ligand in ovarian cancer. We reported positive interim Phase I hMPV+PIV3 vaccine data, supporting the move into a Phase Ib HD escalation study in children. We have begun dosing in Phase I studies for mRNA encoding an antibody against Chikungunya virus and for the immuno-oncology Triplet. INDs are now open for MMA and IL12.

在幻燈片 6 中，以紅色勾勒出輪廓，您可以看到我們的管道在 IPO 後的 90 天內取得了進展。讓我從右到左花一分鐘時間討論這個問題。我們正在計劃 PCV 的 II 期研究和 OX40L 配體在卵巢癌中的 II 期試驗。我們報告了積極的中期 I 期 hMPV+PIV3 疫苗數據，支持進入 Ib 期兒童 HD 升級研究。我們已經開始在 I 期研究中對編碼基孔肯雅病毒抗體和免疫腫瘤三聯體的 mRNA 進行給藥。 MMA 和 IL12 的 IND 現已開放。

On Slide 7, let me give you a quick update about the manufacturing site in Norwood, Massachusetts. We have 4 distinct activities on the site. First, we manufacture clinical material. Since the site opening, we have successfully manufactured clinical-grade mRNA and then moved to formulation and then to filling and finally, labeling of our vials. We are now actively working toward vertical integration of critical raw materials like DNA plasmid used as templates to our mRNA, [buffers] and other raw materials.

在幻燈片 7 上，讓我向您快速介紹一下馬薩諸塞州諾伍德的製造基地。我們在網站上有 4 個不同的活動。首先，我們製造臨床材料。自網站開放以來，我們已經成功製造了臨床級 mRNA，然後轉向配製，然後是灌裝，最後是我們的小瓶貼標。我們現在正積極致力於關鍵原材料的垂直整合，例如用作我們 mRNA、[緩衝液] 和其他原材料模板的 DNA 質粒。

We have also successfully transferred the second capability to Norwood for personalized cancer vaccine, or PCV. We started our PCV clinical trial in 2017 by making a PCV vaccine as a contract manufacturer in the U.S., using Moderna manufacturing process and the robotics we invented to be able to make one lot personalized for one patient. I am pleased to report that we are now capable of making all our PCVs in Norwood for patients in the remainder of Phase I as well for Phase II.

我們還成功地將第二種能力轉移到諾伍德，用於個性化癌症疫苗 (PCV)。我們於 2017 年開始了 PCV 臨床試驗，作為美國的合同製造商生產 PCV 疫苗，使用 Moderna 製造工藝和我們發明的機器人技術，能夠為一名患者定制一批疫苗。我很高興地報告，我們現在能夠在諾伍德為第一階段剩餘部分和第二階段的患者製造我們所有的 PCV。

The third capability transferred to Norwood, which will enable us to reduce costs, is our preclinical robotics that makes all of our research-grade mRNA and formulations.

轉讓給 Norwood 的第三項能力是我們的臨床前機器人技術，它可以製造我們所有的研究級 mRNA 和製劑，這將使我們能夠降低成本。

Let me close my introduction by saying that I'm very proud of the progress our team made in 2018 and in 90 days since our IPO. Momentum and growth are very important to Moderna's success, and it is exciting to see significant progress across the business.

讓我結束我的介紹，我為我們的團隊在 2018 年和 IPO 後 90 天內取得的進步感到非常自豪。勢頭和增長對 Moderna 的成功非常重要，看到整個業務取得重大進展令人興奮。

I would like now to turn to Tal.

我現在想談談塔爾。

Thank you, Stéphane.

謝謝你，斯蒂芬。

Let me now review our progress by modality. If you go ahead to Slide 9 and 10, I'll start with the prophylactic vaccines. A few weeks ago, we reported the Phase I data for our combination vaccine against 2 respiratory viruses, human Metapneumovirus and Parainfluenza Virus 3, or hMPV and PIV3. These are 2 important causes of respiratory tract infections in children and can lead to viral pneumonia and hospitalization, particularly in children under 2 years old. There are currently no approved vaccines against either hMPV or PIV3.

現在讓我按方式回顧一下我們的進展。如果你繼續看幻燈片 9 和 10，我將從預防性疫苗開始。幾週前，我們報告了針對 2 種呼吸道病毒、人偏肺病毒和副流感病毒 3 或 hMPV 和 PIV3 的聯合疫苗的 I 期數據。這是兒童呼吸道感染的 2 個重要原因，可導致病毒性肺炎和住院治療，尤其是 2 歲以下的兒童。目前沒有針對 hMPV 或 PIV3 的批准疫苗。

Now on Slide 11, as we had disclosed, the top line interim data from the study showed that a single vaccination with mRNA-1653 boosted the titers of neutralizing antibodies against both hMPV and PIV3 and that the magnitude of the boost was similar at all dose levels tested. As you would expect, all study participants had some level of baseline neutralizing antibodies against both viruses, yet 1 month after a single mRNA-1653 vaccination, neutralizing titers against hMPV rose to approximately sixfold baseline and those against PIV3 rose to approximately threefold baseline. A second vaccination 1 month later did not further boost antibody titers, suggesting that a single vaccination is already achieving a plateau in the generation of neutralizing antibodies in this pre-exposed population. mRNA-1653 was found to be generally well tolerated. No serious adverse events, adverse events of special interest or adverse events leading to withdrawal were reported. Injection site pain was the most commonly reported adverse event and the most common grade 3 adverse event. The magnitude of responses that we observed is sufficient for us to advance mRNA-1653 to a Phase Ib trial in toddlers, a trial that we are currently designing. I look forward to a further discussion of this point and other aspects of our clinical data in a future medical meeting.

現在在幻燈片 11 上，正如我們所披露的，該研究的主要中期數據表明，單次接種 mRNA-1653 可提高針對 hMPV 和 PIV3 的中和抗體的滴度，並且在所有劑量下提高的幅度相似水平測試。正如您所預料的那樣，所有研究參與者都具有一定水平的針對這兩種病毒的基線中和抗體，但在單次 mRNA-1653 疫苗接種後 1 個月，針對 hMPV 的中和滴度升至基線的大約六倍，針對 PIV3 的中和抗體滴度升至基線的大約三倍。 1 個月後的第二次疫苗接種沒有進一步提高抗體滴度，這表明單次疫苗接種已經在這個預先暴露的人群中達到中和抗體生成的平台。發現 mRNA-1653 通常具有良好的耐受性。沒有報告嚴重不良事件、特別關注的不良事件或導致退出的不良事件。注射部位疼痛是最常報告的不良事件和最常見的 3 級不良事件。我們觀察到的反應幅度足以讓我們將 mRNA-1653 推進到幼兒 Ib 期試驗，這是我們目前正在設計的試驗。我期待在未來的醫學會議上進一步討論這一點以及我們臨床數據的其他方面。

Let me move to our congenital CMV vaccine on Slide 12. This is a vaccine against cytomegalovirus, which is the most common congenital viral infection impacting close to 40,000 infants annually in the United States. Congenital CMV infection can severely affect infant brain development, and it's an important cause of childhood hearing loss. There's currently no approved vaccine to prevent CMV.

讓我轉到幻燈片 12 上的先天性 CMV 疫苗。這是一種針對鉅細胞病毒的疫苗，鉅細胞病毒是美國最常見的先天性病毒感染，每年影響近 40,000 名嬰兒。先天性鉅細胞病毒感染會嚴重影響嬰兒大腦發育，是導致兒童聽力損失的重要原因。目前尚無經批准的預防 CMV 的疫苗。

Our vaccine, mRNA-1647, has enrolled the initial 3-dose levels in the Phase I trial. While we have not yet seen any immunogenicity data, the safety and tolerability data, both in this trial and across our other infectious disease vaccines, suggest that we should be able to dose escalate above 180 microgram. So we are expanding the trial to enroll 2 additional dose levels at higher doses in the range of 300 micrograms. As a reminder, 300 microgram was the top dose that we tested in the hMPV+PIV3 study.

我們的疫苗 mRNA-1647 已在第一階段試驗中登記了最初的 3 劑劑量水平。雖然我們還沒有看到任何免疫原性數據，但本試驗和我們其他傳染病疫苗的安全性和耐受性數據表明，我們應該能夠將劑量提高到 180 微克以上。因此，我們正在擴大試驗，以在 300 微克範圍內的更高劑量範圍內招募 2 個額外的劑量水平。提醒一下，300 微克是我們在 hMPV+PIV3 研究中測試的最高劑量。

Reviewing our overall progress on Slide 13, we have, to date, dosed approximately 950 healthy volunteers enrolled across 7 Phase I trials at doses up to 300 microgram. The emerging safety and tolerability profile has been consistent with that of marketed adjuvanted vaccines. And with a positive readout for hMPV+PIV3, we have now shown promising data from 5 Phase I programs within our prophylactic vaccines modalities, and we continue to make progress. I spoke about our plans for hMPV+PIV3 and CMV.

回顧我們在幻燈片 13 上的總體進展，迄今為止，我們已經對參加 7 項 I 期試驗的大約 950 名健康志願者進行了高達 300 微克的劑量給藥。新出現的安全性和耐受性概況與市售的佐劑疫苗一致。隨著 hMPV + PIV3 的積極讀數，我們現在已經在我們的預防性疫苗模式中展示了來自 5 個 I 期項目的有希望的數據，並且我們繼續取得進展。我談到了我們對 hMPV+PIV3 和 CMV 的計劃。

On Zika, we previously disclosed data for mRNA-1893, which has the potential to be a much more potent follow-on to mRNA-1325. We're in the process of writing the IND for it, and so we'll not be further developing mRNA-1325. Overall, our development of a vaccine against Zika continues to be funded by BARDA under the grant award of approximately $125 million. Lastly, our partners at Merck are preparing to initiate a Phase IIa trial of mRNA-1777, our RSV vaccine.

關於寨卡病毒，我們之前披露了 mRNA-1893 的數據，它有可能成為 mRNA-1325 更有效的後續藥物。我們正在為其編寫 IND，因此我們不會進一步開發 mRNA-1325。總體而言，我們開發針對寨卡病毒的疫苗繼續由 BARDA 根據大約 1.25 億美元的贈款資助。最後，我們在默克的合作夥伴正準備啟動我們的 RSV 疫苗 mRNA-1777 的 IIa 期試驗。

Let me now talk about our cancer vaccine programs. And if you advance to Slide 15, you can clearly see the immunogenicity data from the patient in the Phase I trial of our personalized cancer vaccine. As we previously disclosed, at the second dose level of 0.13 milligram, we were able to show that we elicited new antigens specific T cell responses. To date, we have dosed over 30 patients. At the top dose of 1 milligram, we have not seen any dose-limiting toxicities either for the vaccine alone or in combination with KEYTRUDA. And so we have selected this as the dose to move forward into Phase II.

現在讓我談談我們的癌症疫苗計劃。如果您轉到幻燈片 15，您可以清楚地看到我們個性化癌症疫苗 I 期試驗中患者的免疫原性數據。正如我們之前披露的那樣，在 0.13 毫克的第二劑量水平下，我們能夠證明我們引發了新的抗原特異性 T 細胞反應。迄今為止，我們已經為 30 多名患者給藥。在 1 毫克的最高劑量下，無論是單獨使用疫苗還是與 KEYTRUDA 聯合使用，我們都沒有發現任何劑量限制性毒性。所以我們選擇這個作為進入第二階段的劑量。

On Slide 16, you can see the design of this Phase II study. It is designed to assess whether post-operative adjuvant therapy with mRNA-4157 and KEYTRUDA can improve the recurrence-free survival for melanoma patients when compared to KEYTRUDA alone. We will be testing this in patients who remain at high risk of recurrence despite having had their tumors resected. So the primary endpoint for the study will be recurrence-free survival. And we're planning to have the primary analysis done 12 months after the last subject is enrolled. This protocol has been submitted to FDA.

在幻燈片 16 上，您可以看到此 II 期研究的設計。它旨在評估與單獨使用 KEYTRUDA 相比，用 mRNA-4157 和 KEYTRUDA 進行術後輔助治療是否可以改善黑色素瘤患者的無復發生存期。我們將在儘管切除了腫瘤但仍有高複發風險的患者中進行測試。因此，該研究的主要終點將是無復發生存期。我們計劃在最後一名受試者入組後 12 個月完成初步分析。該協議已提交給 FDA。

As an aside, I would note that we are increasing the neoantigen count in our personalized cancer vaccines from 20 to 34 neoantigens, all still encoded on a single mRNA chain. And we intend to apply this advance to the Phase II study.

順便說一句，我要指出的是，我們正在將個性化癌症疫苗中的新抗原數量從 20 種增加到 34 種新抗原，所有這些新抗原仍然編碼在一條 mRNA 鏈上。我們打算將這一進展應用於 II 期研究。

Let me now turn to our intratumoral immuno-oncology programs, which you can see on Slide 18. We continue to advance the Phase I study of mRNA-2416, which encodes for the OX40 ligand membrane protein and have dosed over 30 patients on this study, some for as many as 10 cycles at doses of up to 8 milligram. We have not seen any dose-limiting toxicities. We have shown that OX40 ligand protein expression in certain injected lesions and have observed regression of injected lesions in 2 patients with advanced ovarian cancer, although these regressions did not meet resist criteria. These observations have motivated us to trigger the Phase II cohort in patients with ovarian cancer.

現在讓我談談我們的腫瘤內免疫腫瘤學項目，您可以在幻燈片 18 上看到。我們繼續推進 mRNA-2416 的 I 期研究，該藥物編碼 OX40 配體膜蛋白，並已對超過 30 名患者進行了該研究, 有些以高達 8 毫克的劑量進行多達 10 個週期。我們沒有發現任何劑量限制性毒性。我們已經證明 OX40 配體蛋白在某些注射病變中的表達，並觀察到 2 名晚期卵巢癌患者的注射病變消退，儘管這些消退不符合抵抗標準。這些觀察結果促使我們啟動了卵巢癌患者的 II 期隊列研究。

The top dose tested in the Phase I trial, 8 milligram, is currently in the dose confirmation stage. And this is the dose we intend for the Phase II cohort in ovarian cancer.

I期試驗的最高劑量8毫克，目前正處於劑量確認階段。這是我們打算用於卵巢癌 II 期隊列的劑量。

Let me talk about mRNA-2752, which encodes the Triplet combination of OX40 ligand interleukin 23 and interleukin 36 gamma. In January, we published new preclinical data in Science Translational Medicine showing that local delivery of the Triplet induced a broad immune response and caused tumor regressions in both injected and distant uninjected lesions in murine models. Additionally, when combined with checkpoint inhibitors, this Triplet was able to induce responses in tumor models that are otherwise unresponsive to checkpoint inhibitors. So these data provide the scientific basis for the Phase I study of mRNA-2752. We initiated dosing late last year, and we have not seen any dose-limiting toxicities in the first dose level and are now began to treat patients at the second dose level.

先說說mRNA-2752，它編碼OX40配體白細胞介素23和白細胞介素36γ的三聯體組合。 1 月，我們在《科學轉化醫學》雜誌上發表了新的臨床前數據，表明在小鼠模型中，三聯體的局部遞送誘導了廣泛的免疫反應，並導致注射和遠處未註射病變的腫瘤消退。此外，當與檢查點抑製劑結合使用時，該三聯體能夠在腫瘤模型中誘導反應，否則這些模型對檢查點抑製劑無反應。所以這些數據為mRNA-2752的I期研究提供了科學依據。我們去年年底開始給藥，我們在第一個劑量水平上沒有發現任何劑量限制性毒性，現在開始以第二個劑量水平治療患者。

Finally, there's always -- there's also been progress with MEDI1191 and mRNA encoding interleukin 12. IL12 is a potent immune modulator whose preclinical profile has generated much interest as a potential anticancer agent. In the past, the clinical development of systemically administered recombinant IL12 has been hampered by systemic toxicity. We have demonstrated preclinically that intratumoral doses of mRNA encoding IL12 can be delivered safely and induced a complete response in multiple murine models, providing the scientific foundation for our partners at AstraZeneca to advance MEDI1191 into the clinic. So indeed, I'm happy to report that AstraZeneca has filed the IND for MEDI1191, and this IND is now open. This trial is designed to evaluate safety and efficacy in patients with solid tumors in combination with a checkpoint inhibitor.

最後，MEDI1191 和編碼白細胞介素 12 的 mRNA 也一直在取得進展。IL12 是一種有效的免疫調節劑，其作為潛在抗癌劑的臨床前特徵引起了人們的極大興趣。過去，全身給藥的重組 IL12 的臨床開發一直受到全身毒性的阻礙。我們已經在臨床前證明編碼 IL12 的 mRNA 的瘤內劑量可以安全地遞送並在多種小鼠模型中誘導完全反應，為我們在阿斯利康的合作夥伴將 MEDI1191 推進臨床提供了科學基礎。事實上，我很高興地報告阿斯利康已經提交了 MEDI1191 的 IND，這個 IND 現已開放。該試驗旨在評估實體瘤患者聯合檢查點抑製劑的安全性和有效性。

On Slide 19, I want to briefly mention the modality of localized regenerative therapeutics. AstraZeneca continues to enroll patients in the randomized Phase IIa trial of AZD8601, which is an mRNA encoding for VEGF-A. As a reminder, the Phase I showed that AZD8601 was well tolerated and led to the translational of functional VEGF-A protein, which caused the dose dependent increase in blood flow where it was injected. These data were recently published in Nature Communications.

在幻燈片 19 上，我想簡單提一下局部再生療法的方式。阿斯利康繼續在 AZD8601 的隨機 IIa 期試驗中招募患者，AZD8601 是一種編碼 VEGF-A 的 mRNA。提醒一下，I 期表明 AZD8601 具有良好的耐受性，並導致功能性 VEGF-A 蛋白的翻譯，這導致注射處的血流劑量依賴性增加。這些數據最近發表在 Nature Communications 上。

Moving next to our systemic secreted therapeutics, let me provide some context on our first program in this modality. On Slide 21, you can see that as we were assessing the biology risk for our systemic secreted therapies, we began the development efforts by including a monoclonal antibody with the goal of inducing transient passive immunity in the recipient. An antibody would represent a complex protein as it requires the co-translation of 2 separate mRNAs and the correct intracellular folding and eventual secretion to the blood of a formed antibody.

接下來是我們的系統性分泌療法，讓我提供一些關於我們在這種模式下的第一個項目的背景信息。在幻燈片 21 上，您可以看到，當我們評估全身分泌療法的生物學風險時，我們開始了開發工作，包括一種單克隆抗體，目的是在接受者中誘導短暫的被動免疫。抗體將代表一種複雜的蛋白質，因為它需要 2 個獨立的 mRNA 的共同翻譯和正確的細胞內折疊，並最終將形成的抗體分泌到血液中。

From a safety perspective, we would expect an antiviral monoclonal antibody to be safe, and we should be able to measure its blood levels. This would then allow us to quantify the PK/PD relationship, in other words, how much mRNA is required to produce how much protein in a relatively straightforward manner. Now this relationship would be of obvious relevance to our pipeline of mRNA medicines for rare diseases, particularly because the lipid nanoparticle delivery system is shared with our rare disease programs as well as with Relaxin. And so we chose an antibody against the Chikungunya virus encoded as mRNA-1944.

從安全的角度來看，我們希望抗病毒單克隆抗體是安全的，我們應該能夠測量它的血液水平。這將使我們能夠量化 PK/PD 關係，換句話說，需要多少 mRNA 才能以相對直接的方式產生多少蛋白質。現在，這種關係顯然與我們用於罕見疾病的 mRNA 藥物管線相關，特別是因為脂質納米顆粒遞送系統與我們的罕見疾病項目以及 Relaxin 共享。因此我們選擇了一種編碼為 mRNA-1944 的抗基孔肯雅病毒抗體。

On Slide 22, you can see the Phase I design for this study. We're conducting it in healthy volunteers. So it should give us a read on the safety and tolerability of the formulation. The pharmacological goal is to determine how much antibody we can produce as a result of systemically administered mRNA and whether 1 day we may be able to offer people with passive immunity against infection by this virus, which today has neither vaccine nor specific therapies available.

在幻燈片 22 上，您可以看到本研究的 I 期設計。我們正在健康的志願者中進行。因此，它應該讓我們了解該配方的安全性和耐受性。藥理學目標是確定我們可以通過全身施用 mRNA 產生多少抗體，以及我們是否有朝一日能夠為人們提供針對這種病毒感染的被動免疫，而目前這種病毒既沒有疫苗也沒有特定的治療方法。

On Slide 22, you can see our progress overall in systemic secreted therapeutics. We recently completed dosing of all 8 subjects in the first cohort of healthy volunteers in this Phase I study. And I look forward to sharing more about this study once we have a complete picture of the data. In addition, we're continuing to move our Fabry and Relaxin programs forward into clinical trials.

在幻燈片 22 上，您可以看到我們在全身分泌療法方面的整體進展。我們最近完成了第一階段研究中第一批健康志願者中所有 8 名受試者的給藥。一旦我們對數據有了完整的了解，我期待著分享更多關於這項研究的信息。此外，我們正在繼續將 Fabry 和 Relaxin 計劃推進到臨床試驗階段。

Finally, let me turn to our systemic intracellular therapeutics. On Slide 25, I'm happy to share today that FDA has given us fast track designation for our methylmalonic acidemia program and has allowed us to open the IND for mRNA-3704, which encodes the mute enzyme missing in children with this disease. We're now preparing to begin the Phase I2 study, and I'll come back to this in just a moment. In addition to mRNA-3704, we continue to progress the preclinical development for both propionic acidemia and phenylketonuria programs with the goal of bringing them into the clinic.

最後，讓我談談我們的系統性細胞內療法。在幻燈片 25 上，我今天很高興地與大家分享，FDA 已為我們的甲基丙二酸血症項目授予快速通道資格，並允許我們開放 mRNA-3704 的 IND，它編碼患有這種疾病的兒童缺失的靜音酶。我們現在正準備開始 I2 期研究，稍後我會回到這個話題。除了 mRNA-3704 之外，我們還繼續推進丙酸血症和苯丙酮尿症項目的臨床前開發，目標是將它們帶入臨床。

On Slide 26, let me describe the design of the MMA study. The primary objective is to evaluate the safety, pharmacodynamics and pharmacokinetics of mRNA-3704 in patients with methylmalonic acidemia. We intend to enroll pediatric patients with elevated plasma MMA levels. And the first dose level will begin with adolescents aged 12 to 18. Once we assess the safety and tolerability of this age group, we then intend to enroll patients who are between the ages of 1 and 18 years old. Following dose escalation, we anticipate the study will move into a dose expansion phase. As a reminder, we have an ongoing natural history study underway for both methylmalonic acidemia and propionic acidemia, which we call the MaP Study. As of the end of February, we have 32 patients enrolled in the study, 20 with MMA and 12 with PA.

在幻燈片 26 上，讓我描述一下 MMA 研究的設計。主要目的是評估 mRNA-3704 在甲基丙二酸血症患者中的安全性、藥效學和藥代動力學。我們打算招募血漿 MMA 水平升高的兒科患者。第一個劑量水平將從 12 至 18 歲的青少年開始。一旦我們評估了該年齡組的安全性和耐受性，我們便打算招募 1 至 18 歲的患者。在劑量遞增後，我們預計該研究將進入劑量擴展階段。提醒一下，我們正在進行一項針對甲基丙二酸血症和丙酸血症的自然歷史研究，我們稱之為 MaP 研究。截至 2 月底，我們有 32 名患者參加了這項研究，其中 20 名患有 MMA，12 名患有 PA。

Let me close on Slide 27 with our pipeline, which illustrates the breadth of our development programs. We're proud of our ability to advance multiple programs in parallel across many different treatment modalities and for different diseases. I look forward to updating you further as we continue to progress our programs.

讓我以我們的管道結束幻燈片 27，它說明了我們開發計劃的廣度。我們為能夠在許多不同的治療方式和不同的疾病中並行推進多個項目而感到自豪。隨著我們繼續推進我們的計劃，我期待著進一步更新您的信息。

With that, I will now turn the call over to Lorence to walk through the financials.

有了這個，我現在將把電話轉給洛倫斯來完成財務。

Thank you, Tal.

謝謝你，塔爾。

Let me turn to Slide 28. In today's press release, we reported our fourth quarter and full year 2018 financial results. Please note, these results are unaudited. We ended 2018 with cash, cash equivalents and investments of $1.7 billion. This compares to $902 million at the end of 2017. This increase was due primarily to financing proceeds, approximately $563 million in net proceeds from our initial public offering in December 2018, approximately $661 million in net proceeds from our preferred stock issuances earlier in 2018 and a $13 million premium associated with the 2018 amended and restated PCV agreement with Merck. All of this was offset partially by the cash used in 2018 to fund operations and for purchases of property and equipment.

讓我轉到幻燈片 28。在今天的新聞稿中，我們報告了 2018 年第四季度和全年的財務業績。請注意，這些結果未經審計。 2018 年底，我們擁有 17 億美元的現金、現金等價物和投資。相比之下，2017 年底為 9.02 億美元。這一增長主要是由於融資收益，2018 年 12 月首次公開募股的淨收益約為 5.63 億美元，2018 年早些時候發行優先股的淨收益約為 6.61 億美元，以及與默克公司於 2018 年修訂和重申的 PCV 協議相關的 1300 萬美元保費。所有這一切都被 2018 年用於資助運營和購買財產和設備的現金部分抵消。

In further discussing our financial results, let me then focus on 2 cash flow metrics, which provide a better view on cash used given the quantity of deferred revenues, stock-based compensation and depreciation embedded in our operating income. Net cash used in operations was approximately $331 million for the full year 2018, which was comparable to 2017. Secondly, cash used for purchases of property and equipment was $106 million for the full year 2018 compared to $58 million for the full year 2017. Of that, cash used specifically related to our Norwood manufacturing facility was $95 million in 2018 compared to $41 million in 2017.

在進一步討論我們的財務業績時，讓我重點關注 2 個現金流量指標，考慮到我們的營業收入中包含的遞延收入、基於股票的補償和折舊的數量，這些指標可以更好地了解現金使用情況。 2018 年全年運營使用的現金淨額約為 3.31 億美元，與 2017 年持平。其次，2018 年全年用於購買財產和設備的現金為 1.06 億美元，而 2017 年全年為 5800 萬美元。也就是說，2018 年與我們諾伍德製造工廠特別相關的現金為 9500 萬美元，而 2017 年為 4100 萬美元。

Revenue for the full year 2018 was $135 million as compared to $206 million for 2017. The decrease was mainly attributable to the termination of the Alexion strategic alliance arrangement in October 2017, which caused an accelerated recognition of deferred revenue in 2017. Also, there was a decrease in grant revenue from the BARDA contract, primarily due to revisions in the Zika program leading to a focus on preclinical study of the mRNA-1893, our follow-on to mRNA-1325. The decreases were partially offset by increases in collaboration revenue from AstraZeneca and Merck.

2018 年全年收入為 1.35 億美元，而 2017 年為 2.06 億美元。減少的主要原因是 Alexion 戰略聯盟安排於 2017 年 10 月終止，導致 2017 年遞延收入的確認加速。此外，還有BARDA 合同的贈款收入減少，這主要是由於 Zika 項目的修訂導致專注於 mRNA-1893 的臨床前研究，這是我們對 mRNA-1325 的後續研究。減少部分被阿斯利康和默克公司的合作收入增加所抵消。

R&D expenses for full year 2018 were approximately 404 -- $454 million compared to $410 million for 2017. The increase was primarily due to an increase in personnel-related costs, including stock-based compensation, mainly driven by an increase in the number of employees supporting our R&D programs, an increase in consulting and outside services and an increase in facility and equipment-related costs.

2018 年全年的研發費用約為 404-4.54 億美元，而 2017 年為 4.1 億美元。增加的主要原因是與人事相關的費用增加，包括股票薪酬，這主要是由於員工人數增加所致支持我們的研發計劃，諮詢和外部服務的增加以及設施和設備相關成本的增加。

G&A expenses for full year 2018 were approximately $94 million compared to $65 million in 2017. This increase was mainly attributable to increases in personnel-related costs, including stock-based compensation, driven by an increase in the number of employees and consulting an outside services, all of which were in support of our public company readiness.

2018 年全年的 G&A 費用約為 9400 萬美元，而 2017 年為 6500 萬美元。這一增長主要是由於員工人數增加和諮詢外部服務導致人員相關成本增加，包括股票薪酬，所有這些都支持我們的上市公司準備。

I'll finish this slide with our expectations for our cash use in 2019. Currently, we expect that we will finish the year with between $1.15 billion and $1.2 billion in cash, cash equivalents and investments. Our use of cash is rising from 2018 driven by our advancing pipeline and the associated development and supply costs, offset by a decline in our expected capital expenditures after last year's completion of Norwood.

我將以我們對 2019 年現金使用的預期結束這張幻燈片。目前，我們預計我們將以 11.5 億美元至 12 億美元的現金、現金等價物和投資結束這一年。在我們推進管道和相關開發和供應成本的推動下，我們的現金使用量從 2018 年開始增加，但在去年完成 Norwood 後我們預期的資本支出下降所抵消。

Two last points before I hand the call back over to Stéphane. As noted in our press release, we're pleased that we are to be added to the Russell 1000 and Russell 3000 indices effective March 18. And lastly, I'm very excited to welcome Lavina Talukdar to our team as Head of Investor Relations effective April 1. Lavina joined us from ADIA and a long career on the buy side.

在我將電話轉回給 Stéphane 之前的最後兩點。正如我們的新聞稿中所述，我們很高興我們將於 3 月 18 日加入羅素 1000 和羅素 3000 指數。最後，我非常高興地歡迎 Lavina Talukdar 作為投資者關係主管加入我們的團隊4 月 1 日。Lavina 從 ADIA 加入我們，並在買方擁有長期的職業生涯。

Now let me turn it over to Stéphane.

現在讓我把它交給 Stéphane。

Thank you, Lorence.

謝謝你，洛倫斯。

Moving to Slide 29. To close our remarks, I would like to reiterate that the company is very focused on execution. I hope our recent progress gives you a sense for that focus, which is essential to both our culture and our mission. Three priorities. Number one, advancing the development pipeline and getting to clinical readouts as fast as we can with high quality. Number two, investing in new development candidates in the 6 existing modalities and moving them to our development pipeline. Number three, investing in new modalities.

轉到幻燈片 29。為了結束我們的發言，我想重申公司非常注重執行。我希望我們最近的進展能讓您了解這種專注，這對我們的文化和使命都至關重要。三個優先事項。第一，推進開發流程並儘可能快地獲得高質量的臨床數據。第二，在 6 種現有模式中投資新的開發候選項目，並將它們轉移到我們的開發管道中。第三，投資新模式。

If you can turn to Slide 30, which shows our anticipated clinical next steps. 2019 and 2020 are going to be important for Moderna. We expect additional Phase I readouts and multiple Phase II starts and readouts.

如果你能翻到幻燈片 30，它顯示了我們預期的臨床後續步驟。 2019 年和 2020 年對 Moderna 來說非常重要。我們期待更多的第一階段讀數和多個第二階段的開始和讀數。

Turning to Slide 31. We would like to announce 2 important investor events for Moderna this year that we hope you can join. We will host the Science Day in Cambridge on May 7, led by Dr. Stephen Hoge; and we'll host the R&D Day in New York City on September 12, led by Dr. Tal Zaks.

轉到幻燈片 31。我們想宣布今年為 Moderna 舉辦的 2 場重要投資者活動，希望您能參加。我們將於 5 月 7 日在劍橋舉辦科學日活動，由 Stephen Hoge 博士領導；我們將於 9 月 12 日在紐約市舉辦研發日活動，由 Tal Zaks 博士主持。

On Slide 32, you have an update of Moderna. I believe that Moderna is operating from a place of tremendous strength. Enabled by our mRNA platform, our large development pipeline continues to progress based on the data we are generating. We have now 4 programs in or planning for Phase II, 6 positive Phase I readouts, 5 ongoing Phase I trials, 3 open INDs.

在幻燈片 32 上，您有 Moderna 的更新。我相信 Moderna 的運營實力非常強大。在我們的 mRNA 平台的支持下，我們的大型開發管道將根據我們生成的數據繼續推進。我們現在有 4 個項目正在或計劃進行第二階段，6 個積極的第一階段讀數，5 個正在進行的第一階段試驗，3 個開放的 IND。

If we look at the pipeline by prophylactic area, I'm very proud that we now have 5 immuno-oncology programs: OX40 ovarian and PCV preparing for Phase II, then Triplet is continuing dose escalation in Phase I and 2 open INDs, KRAS with Merck and IL12 with AstraZeneca. Four rare disease programs: MMA, PA, PKU and Fabry. Three vaccines for large unmet medical needs: RSV, CMV and the combo, hMPV+PIV3.

如果我們按預防領域看管線，我很自豪我們現在有 5 個免疫腫瘤學項目：OX40 卵巢和 PCV 為 II 期做準備，然後 Triplet 在 I 期和 2 個開放的 IND 中繼續劑量遞增，KRAS 與Merck 和 IL12 與 AstraZeneca。四個罕見病項目：MMA、PA、PKU 和 Fabry。用於大量未滿足醫療需求的三種疫苗：RSV、CMV 和組合 hMPV+PIV3。

More than 750 talented employees, we are committed to leading a modern science. The 200,000 square foot manufacturing site in Norwood, which is a strategic asset for Moderna. This capability will enable us to scale and provide an important competitive advantage to Moderna to keep executing and accelerating. The strong balance sheet with $1.7 billion of cash, this provides multiyears of financing for operations and investments in our future.

我們擁有 750 多名才華橫溢的員工，致力於引領現代科學。位於諾伍德的 200,000 平方英尺製造基地是 Moderna 的戰略資產。這種能力將使我們能夠擴展並為 Moderna 提供重要的競爭優勢，以保持執行和加速。擁有 17 億美元現金的強勁資產負債表，為我們未來的運營和投資提供了多年的融資。

On Slide 33, our mission. We know that we have a special opportunity. And we are committed to delivering on the promise of our science and bringing forward a new class of medicines for patients in need. I'd like to end our remarks by thanking the many people who participate in our clinical studies, including patients, healthy volunteers and physicians.

在幻燈片 33 上，我們的任務。我們知道我們有一個特殊的機會。我們致力於兌現我們科學的承諾，並為有需要的患者提供一類新的藥物。最後，我想感謝參與我們臨床研究的許多人，包括患者、健康志願者和醫生。

With that, we'll now be happy to take any questions. Operator?

有了這個，我們現在很樂意回答任何問題。操作員？

(Operator Instructions) And our first question comes from the line of Matthew Harrison of Morgan Stanley.

（操作員說明）我們的第一個問題來自摩根士丹利的馬修哈里森。

I guess two from me. Can you talk about first for PCV, why you chose that specific indication? And just -- because maybe I'm not familiar with, what's the typical recurrence-free survival for patients that you're enrolling here? And maybe you could just talk about how the study is powered or what you're hoping to achieve at the PCV combination versus that. And then, a second question. Just given the fact that you've pushed OX40 ligand into a Phase II study on, I mean, how should we think about that program versus the triple? And is there a point in which you have to pick one?

我想我有兩個。能不能先說說PCV，為什麼選擇那個具體的適應症？只是——因為我可能不熟悉，你在這裡招募的患者的典型無復發生存期是多少？也許你可以談談這項研究是如何提供動力的，或者你希望在 PCV 組合中實現什麼。然後，第二個問題。鑑於您已將 OX40 配體推入 II 期研究，我的意思是，我們應該如何考慮該項目與三聯項目？有沒有你必須選擇一個的點？

Thank you. This is Tal. Let me answer them in sequence. So let's start with the adjuvant trial for PCV. The reason we picked this indication is because I think it's generally true across anticancer drugs that when a drug is effective, the magnitude of effect tends to be higher and lower in earlier lines of treatment and even more so in the adjuvant setting. And you would expect this to be true for melanoma and for immunotherapy, specifically because you need some time in a healthy immune system for the patient to be able to react. It is also notable, I think, that most, if not all, of the data to date in similar approaches has been developed in adjuvant melanoma. So it's a place where I think, overall, the likelihood of success is highest. In terms of this patient population, the -- in recent studies, I think the recurrence-free survival of patients with advanced melanoma that has been resected has been around 33% to 40%, if you look at recent studies. Our underlying assumptions since we're taking a slightly high-risk patient population was that the baseline rate should be above 45%. The trial is powered at about 85% power with a one-sided alpha of 0.1 as is typical for Phase II PoC studies to show a hazard ratio of about 0.5. So I think typical stats, more or less, for a proof-of-concept study. I would note that the study has randomization of 2 to 1. And the reason that we're enrolling more patients on the treatment arm with the vaccine is because there is a good body of recent evidence on how patients perform in terms of just KEYTRUDA alone. And our partners, Merck, have all that experience at hand from their recent Phase III trials in this setting, which led to the approval of KEYTRUDA in the setting. So we should be able to leverage not just the control arm on this study, but a wider body of data as a comparator for this study, helping us overall with the sense of power here. So that's on PCV. For the OX40 ligand, it's a good question and one that obviously we wrestle with as well. Like any cancer doc, when you see a signal of activity, you feel compelled to go and see if there's real benefit there for patients. Ultimately, OX40 ligand is ahead of the Triplet in terms of the clinical trials. Time will tell what is the magnitude of activity that we see in this trial and what type of activity we can see with the Triplet. So I think it's too early to predict how this will play out. I think for now, we are following the clinical signals where we see them as one is -- wont to do for the benefit of patients.

謝謝。這是塔爾。讓我按順序回答。因此，讓我們從 PCV 的輔助試驗開始。我們選擇這個適應症的原因是因為我認為抗癌藥物通常是這樣的，即當一種藥物有效時，效果的幅度在早期治療中往往會越來越高和越來越低，在輔助治療中更是如此。你會期望黑色素瘤和免疫療法也是如此，特別是因為你需要一些時間在健康的免疫系統中，以便患者能夠做出反應。我認為，值得注意的是，迄今為止，大多數（如果不是全部）類似方法的數據都是在輔助黑色素瘤中開發的。所以我認為，總體而言，這是一個成功可能性最高的地方。就這個患者群體而言，在最近的研究中，我認為已切除的晚期黑色素瘤患者的無復發生存率約為 33% 至 40%，如果你看一下最近的研究。由於我們接受的是稍微高風險的患者群體，因此我們的基本假設是基線率應高於 45%。該試驗以約 85% 的功率供電，單側 alpha 為 0.1，這是典型的 II 期 PoC 研究顯示約 0.5 的風險比。所以我認為典型的統計數據，或多或少，用於概念驗證研究。我要指出的是，該研究的隨機化比例為 2 比 1。我們在疫苗治療組招募更多患者的原因是因為最近有大量證據表明患者僅在 KEYTRUDA 方面的表現如何.我們的合作夥伴默克公司從他們最近在這種情況下進行的 III 期試驗中獲得了所有經驗，這導致了 KEYTRUDA 在這種情況下的批准。因此，我們不僅應該能夠利用這項研究的控制臂，而且還應該能夠利用更廣泛的數據作為這項研究的比較，幫助我們在這裡全面了解權力感。這就是PCV。對於 OX40 配體，這是一個很好的問題，顯然我們也在努力解決這個問題。像任何癌症醫生一樣，當您看到活動信號時，您會感到有必要去看看那裡是否對患者有真正的好處。最終，OX40 配體在臨床試驗方面領先於 Triplet。時間會告訴我們在這個試驗中看到的活動強度是多少，以及我們可以用 Triplet 看到什麼類型的活動。所以我認為現在預測這將如何發展還為時過早。我認為目前，我們正在按照我們認為的臨床信號進行跟踪——通常是為了患者的利益。

And Tal, can I just ask a follow-up on the Triplet? I mean, I assume the dosing strategy there is to go a little bit slower given some of the cytokines you have involved as well. I mean, will that one maybe even take longer to potentially catch up or have similar data to that OX40 ligand alone?

塔爾，我可以問一下關於三胞胎的後續行動嗎？我的意思是，鑑於您也涉及一些細胞因子，我假設劑量策略會稍微慢一些。我的意思是，那個人可能需要更長的時間才能趕上或擁有與單獨的 OX40 配體相似的數據嗎？

Not necessarily. So I think yes, we are starting it at a somewhat lower dose than we started with 0X40 ligand alone because OX40 ligand is a membrane-bound protein, you would expect less risk. And of course, when you've got locally secreted cytokines, you want to dose them at a dose that has a local activity without spillover to systemic toxicity. So there's probably a couple more dose cohorts in that study, but I don't think it's going to be a significant delay relative to our experience with OX40 ligand.

不必要。所以我認為是的，我們開始時的劑量比單獨使用 0X40 配體時要低一些，因為 OX40 配體是一種膜結合蛋白，您會期望風險更低。當然，當您獲得局部分泌的細胞因子時，您希望以具有局部活性且不會溢出至全身毒性的劑量給予它們。因此，該研究中可能還有幾個劑量組，但我認為相對於我們使用 OX40 配體的經驗，這不會有明顯的延遲。

Our next question comes from the line of Salveen Richter of Goldman Sachs.

我們的下一個問題來自高盛的 Salveen Richter。

Two questions from me as well. With regard to the PCV program, you mentioned that you've increased the neoantigen count at the cassette from 20 to 34. Just wanted to get your thoughts around that and whether you think that's a broad enough sample set. And then secondly, on the systemic therapeutic modalities. Can you help us understand with regard to the Chikungunya program, you're looking at a single dose right now but at one point, you looked to multiple doses. How should we think about the safety profile in the context of derisking this program based on the redosing aspect? And then a second level or the second systemic therapeutic question is, when could we see MMA data?

我也有兩個問題。關於 PCV 項目，你提到你已經將盒中的新抗原計數從 20 增加到 34。只是想了解一下你的想法，以及你是否認為這是一個足夠廣泛的樣本集。其次，關於全身治療方式。您能否幫助我們了解基孔肯雅熱計劃，您現在正在研究單劑，但在某個時候，您考慮了多劑。在基於重做方面降低該程序風險的背景下，我們應該如何考慮安全性？然後第二個層次或第二個系統性治療問題是，我們什麼時候可以看到 MMA 數據？

Thank you for those. Let me start in the sequence of that you asked. The neoantigen number, so look, it -- what we know from immuno-oncology is that it really only takes 1 antigen if you have a sufficiently potent immune response to lead to cancer aggression. The question is, how do you increase the probability of getting the right one? If you look at the average number of mutations that occur within coding sequences and then get expressed in proteins, depending on the tumor type, you can have up to, typically, in the order of a couple of a hundred is sort the number at the median range. So increasing the number, I think, overall, should increase the probability of success. Now you have to do it within the context of what you think is feasible for the technology. One of the benefits of having it all included in mRNA is that going from 20 to 34 in this case doesn't materially affect our complexity of either process or cost of goods. It just took us some optimization of the mRNA and what we're doing. So I think it's a step in the right direction in terms of how one thinks about eliciting the most potent immune response possible. It will be obviously difficult to nail down what is the right number. We're trying to give this vaccine the best possible opportunity to succeed for patients here. In terms of how to think about single dose versus multiple doses and the safety, it's a good question. The place for us to start is at a place where we can have the clearest understanding of what the safety profile would be. And so that's why we started with a single ascending dose in healthy people for approaching that should be innocuous in and of itself. And that's why I think the Chikungunya, we view it as a very informative first step. It's a good question on the safety of single versus repeated doses. If I look at the totality of our preclinical models, I don't think we have a sense that giving multiple doses should give you a different safety profile than giving a single dose. And if you look at typical adverse event profiles for injected medicines, whether they be antibodies or lipid nanoparticles, the sort of acute reactogenicity or hypersensitivity reactions, should you see them, don't necessarily increase over time. In some cases, they decrease over time. In some cases, it just happens sporadically. So I'm not sure that I expect a different safety profile on repeat dose versus single dose. And that's how we think about the relevance of this first program to the rest of our rare disease repeat dose programs. Your last question on when can we expect data from MMA? Look, we're not forward guiding. Obviously, this is a very rare patient population. We have to start in a place that balances the age of the patients and the age of where actually disease is prevalent, which -- what led us to this adolescent group. What we are committed to is being transparent at every stage of the way, where we are in terms of enrollment until you'll see us give you regular updates on our progress.

謝謝你的那些。讓我按照你問的順序開始。新抗原的數量，所以看，它——我們從免疫腫瘤學中了解到，如果你有足夠強大的免疫反應導致癌症侵襲，它實際上只需要一種抗原。問題是，你如何增加得到正確答案的概率？如果你查看編碼序列中發生的突變的平均數量，然後在蛋白質中表達，根據腫瘤類型，你可以有多達，通常，大約幾百個是排序的數字中值範圍。因此，我認為，總體而言，增加人數應該會增加成功的可能性。現在你必須在你認為技術可行的範圍內進行。將其全部包含在 mRNA 中的好處之一是，在這種情況下，從 20 到 34 不會對我們的流程或商品成本的複雜性產生實質性影響。我們只是對 mRNA 和我們正在做的事情進行了一些優化。所以我認為，就人們如何思考引發最強大的免疫反應而言，這是朝著正確方向邁出的一步。顯然很難確定什麼是正確的數字。我們正在努力為這種疫苗提供最好的機會，讓這裡的患者獲得成功。就如何考慮單劑量與多劑量以及安全性而言，這是一個很好的問題。我們的起點是我們可以最清楚地了解安全概況的地方。因此，這就是為什麼我們開始在健康人群中使用單次遞增劑量來接近它本身應該是無害的。這就是為什麼我認為基孔肯雅熱，我們將其視為非常有用的第一步。這是一個關於單劑量與重複劑量的安全性的好問題。如果我看一下我們臨床前模型的整體情況，我認為我們不認為多劑量給藥應該給您帶來與單劑量給藥不同的安全性。如果您查看注射藥物的典型不良事件概況，無論它們是抗體還是脂質納米顆粒，那種急性反應原性或超敏反應，如果您看到它們，不一定會隨著時間的推移而增加。在某些情況下，它們會隨著時間的推移而減少。在某些情況下，它只是偶爾發生。所以我不確定我是否期望重複劑量與單次劑量的安全性不同。這就是我們如何考慮第一個項目與我們其他罕見病重複劑量項目的相關性。關於我們何時可以從 MMA 獲得數據的最後一個問題？看，我們不是前瞻性的指導。顯然，這是一個非常罕見的患者群體。我們必須從一個平衡患者年齡和實際疾病流行年齡的地方開始，正是這一點讓我們找到了這個青少年群體。我們承諾在整個過程的每個階段都保持透明，在您看到我們定期向您更新我們的進展之前，我們在註冊方面都是如此。

Our next question comes from the line of Cory Kasimov of JPMorgan.

我們的下一個問題來自摩根大通的 Cory Kasimov。

This is Matthew on for Cory. Just a follow-up on the PCV program. I'm curious if you can help us better understand what informs your decision from an efficacy perspective to move ahead to the Phase II trial specifically at the 1-mg dose cohort.

這是科里的馬修。只是 PCV 計劃的後續行動。我很好奇您是否可以幫助我們更好地理解是什麼讓您從療效的角度做出決定，特別是在 1 mg 劑量隊列中推進 II 期試驗。

Yes. It's a great question. We are talking about cancer vaccines, which obviously are a tough place to predict efficacy, historically. I think it's a combination of two things. Our sense of the totality of the immunogenicity data that we've seen to date in our program, we've disclosed for 1 patient; the rest we'll disclose when there's a body of evidence that's sufficient to really -- had a scientific discourse at a medical meeting. But the totality of our data combined with our sense of the tolerability and safety profile at the 1 milligram dose, I think has given us and our partners, Merck, the confidence that we are ready to go to Phase II. In terms of what went -- what it takes to plan your Phase II, we've always been committed to ensuring that we test this personalized cancer vaccine in a way that is as definitive as possible, which is why you see us launch relatively early a randomized Phase II study. We will be continuing to expand the Phase I experiment with additional cohorts to further characterized both the immunogenicity and the potential for benefit in a single arm sense. But if you want a definitive result, you run a randomized Phase II. And that's what we're doing here.

是的。這是一個很好的問題。我們談論的是癌症疫苗，從歷史上看，這顯然是一個很難預測療效的地方。我認為這是兩件事的結合。我們對迄今為止在我們的計劃中看到的免疫原性數據的整體感覺，我們已經披露了 1 名患者；其餘的我們將在有大量證據足以真正 - 在醫學會議上進行科學討論時披露。但我們的全部數據加上我們對 1 毫克劑量的耐受性和安全性的認識，我認為已經給了我們和我們的合作夥伴默克公司信心，我們已經準備好進入第二階段。就發生了什麼——計劃你的第二階段需要什麼，我們一直致力於確保我們以盡可能確定的方式測試這種個性化癌症疫苗，這就是為什麼你看到我們相對較早推出的原因一項隨機的 II 期研究。我們將繼續擴大 I 期實驗，增加更多的隊列，以進一步表徵單臂感覺的免疫原性和獲益潛力。但是如果你想要一個明確的結果，你可以運行一個隨機的第二階段。這就是我們在這裡所做的。

Great. And then just quickly on the CMV vaccine program. Does the opening of the 300-microgram dose cohort affect time lines for when we should expect to see initial immunogenicity data?

偉大的。然後快速啟動 CMV 疫苗計劃。 300 微克劑量隊列的開始是否會影響我們預計何時會看到初始免疫原性數據的時間線？

Yes. I think that's a fair question. And I would anticipate it will delay somewhat the time line. We have made great progress to date. We've completed enrollment in the first 3 cohorts. It is a healthy volunteer study. So our ability to accrue or recruit patients on time and analyze the data has been exactly where we wanted. But I think the nature of these studies is that you first get a sense of tolerability and only later of immunogenicity. So I'd hate to come to the end of the study and figured that I'd underdosed, which is why we've decided to take a little bit longer and make sure we're exploring the full range of doses that we think is appropriate.

是的。我認為這是一個公平的問題。我預計它會稍微延遲時間線。迄今為止，我們取得了很大進展。我們已經完成了前 3 個隊列的註冊。這是一項健康的志願者研究。因此，我們按時積累或招募患者並分析數據的能力正是我們想要的。但我認為這些研究的本質是你首先了解耐受性，然後才了解免疫原性。所以我不想在研究結束時認為我劑量不足，這就是為什麼我們決定花更長的時間並確保我們正在探索我們認為的全部劑量範圍合適的。

Our next question comes from the line of Ying Huang of Bank of America Merrill Lynch.

我們的下一個問題來自美銀美林的黃穎。

The first one is on the PCV program. Tal, can you comment whether you observed any epitope spreading in the Phase I portion? And also, can you comment on your manufacturing needle-to-needle time line now that everything is brought in-house? And then I have a second question on the OX40 ligand program. So do you believe that you need go to a higher dose for OX40 ligand? Or do you think maybe, ultimately, you need a combination, the Triplet, to achieve meaningful clinical activity here?

第一個是關於 PCV 程序。 Tal，你能評論一下你是否在第一階段部分觀察到任何表位擴散嗎？而且，既然一切都在內部進行，您能否評論一下您的製造針對針時間表？然後我有關於 OX40 配體計劃的第二個問題。那麼您是否認為需要更高劑量的 OX40 配體？或者您是否認為，最終，您可能需要一個組合，即三聯體，以在這裡實現有意義的臨床活動？

Thank you for those. Let's start with antigen spreading. I think that's a tough one. We are not -- to be fair, the -- majority of the trials for our translational experiments has been to ascertain whether we can actually elicit the immunogenicity against the new epitopes for which we encode. So the magnitude, I think, overall, of data here is not going to be as scientifically I think rewarding as you might want in terms of answering such a multitude of questions in this first Phase I, really. The goal of Phase I was to establish a dose where we believe there is immunogenicity against that which we encode. Some of those questions, we will answer I think later in the program. And you'll see some of that data as we get a sufficient body of evidence to be able to share it with the broader scientific community. The turnaround time, we are currently at around 50 days, I'd say, needle-to-needle. We're continuously looking at ways to improve it. As you would expect, bringing it to Norwood should enable us to tighten the time line. But this will be a continuous evolution over time as we look -- every day matters here and we look at hours and days as a metric to continuously improve there. In terms of the dose for OX40 ligand, I think that to date, we've seen protein expression in the injected lesions. So it's hard to determine what is the optimal dose. I think the fact that we've been able to show some local pharmacology when you actually look at the stained tissue gives us a sense that we are activating the pathway in the way that we hope to. And to your point, I think that -- or from a scientific perspective, you would expect that you would need additional signals, whether they are additional local signals like in the Triplet or potentially, even the additional of the systemic checkpoint inhibitor to see the maximal activity of this type of therapy. And I think that's been borne out for other approaches in this space as well.

謝謝你的那些。讓我們從抗原擴散開始。我認為這是一個艱難的過程。我們不是——公平地說，我們的轉化實驗的大部分試驗是為了確定我們是否真的能引發針對我們編碼的新表位的免疫原性。因此，我認為，總體而言，就第一階段回答如此眾多的問題而言，我認為這裡的數據量在科學上不會像你想要的那樣有價值，真的。第一階段的目標是建立一個我們認為對我們編碼的東西具有免疫原性的劑量。其中一些問題，我想稍後會在節目中回答。當我們獲得足夠的證據以便能夠與更廣泛的科學界分享時，你會看到其中的一些數據。周轉時間，我們目前在 50 天左右，我想說，針對針。我們一直在尋找改進它的方法。如您所料，將它帶到諾伍德應該能讓我們縮短時間。但正如我們所看到的那樣，這將是隨著時間的推移而不斷發展的——這裡的每一天都很重要，我們將小時和天數視為在那裡不斷改進的指標。就 OX40 配體的劑量而言，我認為到目前為止，我們已經在註射的病灶中看到了蛋白質表達。所以很難確定什麼是最佳劑量。我認為，當您實際查看染色組織時，我們已經能夠展示一些局部藥理學，這讓我們感覺我們正在以我們希望的方式激活該通路。就你的觀點而言，我認為——或者從科學的角度來看，你會期望你需要額外的信號，無論它們是額外的局部信號，比如三聯體還是潛在的，甚至是額外的系統檢查點抑製劑來觀察這種療法的最大活性。我認為這一點也已在該領域的其他方法中得到證實。

And our next question comes from the line of Geoff Meacham of Barclays.

我們的下一個問題來自巴克萊銀行的 Geoff Meacham。

Just have a couple. The first one is an active comparator study in PCV, obviously, is a high bar, but it really is the best way to achieve proof-of-concept. The question is philosophically, should this be the template that we should expect going forward in oncology or really wherever you're targeting indications where there is an existing standard of care? And the second question is on manufacturing. I know the Norwood facility is obviously built for scale up. But just given the breadth of the pipeline, is there ample capacity, for example, to get to pivotal or large-scale studies in all your disclosed programs? Or do you think, ultimately, you need to expand even more down the road?

只要有一對。第一個是 PCV 中的主動比較器研究，顯然，這是一個很高的標準，但它確實是實現概念驗證的最佳方式。這個問題是哲學上的，這應該是我們應該期待在腫瘤學中前進的模板，還是真的任何你針對有現有護理標準的適應症的地方？第二個問題是關於製造業的。我知道諾伍德工廠顯然是為擴大規模而建造的。但是，考慮到管道的廣度，是否有足夠的能力，例如，在所有公開的項目中進行關鍵或大規模研究？或者你認為，最終，你需要進一步擴張嗎？

Thank you. Let me take the first question in terms of active comparative study. Clinical development remains artisanal. The truth is that it depends on the situation. I think in oncology, in large indications, there are instances where the signal is unquestionable there. And you go on the single arm and everybody agrees that yes, you're bringing benefits to patients. Traditionally, one expects at some point a randomized trial. And I think to make sort of broad statements of what's always applicable is hard certainly for a company that's so early in this stage. And I would further note that if you look across our pipeline, some of the indications we're targeting are extremely rare indications in which it's virtually impossible to conduct a full randomized study as you would for more prevalent indications. So I don't think I can really give you a more satisfactory answer than that. In terms of our manufacturing capacity, let me ask Stéphane to take that one.

謝謝。讓我從主動比較研究的角度來回答第一個問題。臨床開發仍然是手工的。事實是，這取決於情況。我認為在腫瘤學中，在大的適應症中，有些情況下信號是毋庸置疑的。你繼續單臂，每個人都同意，是的，你給病人帶來了好處。傳統上，人們期望在某個時候進行隨機試驗。而且我認為，對於處於這個階段如此早期的公司來說，對始終適用的內容做出廣泛的陳述肯定是困難的。我會進一步指出，如果你看看我們的管道，我們針對的一些適應症是極其罕見的適應症，在這些適應症中，幾乎不可能像對更普遍的適應症那樣進行全面的隨機研究。所以我想我真的不能給你比這更令人滿意的答案了。就我們的製造能力而言，讓我讓 Stéphane 接受那個。

Yes. Thanks, Tal. So regarding manufacturing, the thing that is very clear is that the vision and the mission of Norwood is to be a development site for long term. Having said that, as you know, managing risk is really important to the team. And so what we have done as we designed in this Norwood from a utility standpoint, it can accommodate Phase III and launches. It is not a launch probably today for commercial, but we have road maps and time lines that have been developed by the team so that people who have to decide who gets ready for Norwood for launches, we could do that. We have a, also, of course, a second plan that give us full optionality, which is we have enabled a commercial contract manufacturing organization in the U.S., which is doing commercial product, as we speak. They are -- acted as our backup for Norwood. And so as we get closer to launch and to running pivotals, we could decide whether rapidly enable Norwood for our first few launches or use a contract manufacturer. In the long term, our goal will be to build a commercial plant. But for obvious reason of managing risk, we did not want to do that until our first product approved. And so we have a good path forward of how we manage the next phase of our growth dealing with pivotal and commercial.

是的。謝謝，塔爾。因此，關於製造業，非常清楚的一點是，諾伍德的願景和使命是成為一個長期的開發基地。話雖如此，如您所知，管理風險對團隊來說非常重要。因此，從公用事業的角度來看，我們在諾伍德設計時所做的，它可以適應第三階段和發射。這可能不是今天的商業發布，但我們有團隊制定的路線圖和時間表，以便那些必須決定誰為諾伍德的發布做好準備的人，我們可以做到這一點。當然，我們還有第二個計劃，讓我們有完全的選擇權，那就是我們已經在美國啟用了一個商業合同製造組織，正如我們所說的那樣，它正在做商業產品。他們是——充當我們對諾伍德的支持。因此，當我們接近發布和運行關鍵點時，我們可以決定是快速啟用 Norwood 進行我們的前幾次發布，還是使用合同製造商。從長遠來看，我們的目標將是建立一個商業工廠。但出於管理風險的明顯原因，在我們的第一個產品獲得批准之前，我們不想這樣做。因此，我們有一條很好的前進道路，可以讓我們如何管理下一階段的增長，處理關鍵和商業問題。

Our next question comes from the line of Ted Tenthoff of Piper Jaffray.

我們的下一個問題來自 Piper Jaffray 的 Ted Tenthoff。

My question has to do with hMPV+PIV3. And congrats on that good Phase I data, really clean safety profile. What are some of the special considerations or how should we be thinking about this toddler study? Obviously, safety is going to be paramount. But are there anything else we should be considering like when you dose or things like that, that maybe learned sort of from the immunogenicity curves from the healthy?

我的問題與 hMPV+PIV3 有關。並祝賀第一階段的良好數據，非常乾淨的安全概況。有哪些特殊考慮因素或我們應該如何考慮這項幼兒研究？顯然，安全將是最重要的。但是還有什麼我們應該考慮的，比如當你給藥時或類似的事情，這可能是從健康人的免疫原性曲線中學到的？

Thank you for that question. I think there are several relevant considerations here. The first is to note that the first exposure in the pediatric population will still be in 0 positives. We have to make sure that because of the history, primarily of inactivated RCV back in the day, there is a theoretical concern of disease exacerbation. And so one always starts by evaluating safety in 0-positive toddlers. I think the nice thing for the Phase I or for the data is because we reached the plateau so soon, we have a wide margin of doses that we could test that should give us a read on safety and tolerability in these 0-positive toddlers. I can't comment further because we're still in the design phases of the study. And obviously, we will have to sit down with the regulatory authority as well before we can commit to what that is.

謝謝你提出這個問題。我認為這裡有幾個相關的考慮因素。首先要注意的是，兒科人群的首次接觸仍為 0 陽性。我們必須確保，由於過去主要是滅活 RCV 的歷史，理論上存在疾病惡化的問題。因此，人們總是從評估 0 陽性幼兒的安全性開始。我認為第一階段或數據的好處是因為我們很快就達到了穩定期，我們有很大的劑量範圍可以測試，這應該讓我們了解這些 0 陽性幼兒的安全性和耐受性。我不能進一步評論，因為我們仍處於研究的設計階段。顯然，在我們承諾這是什麼之前，我們也必須與監管機構坐下來。

Our next question comes from the line of Hartaj Singh of Oppenheimer & Co.

我們的下一個問題來自 Oppenheimer & Co. 的 Hartaj Singh。

I just have a couple of questions, one general and one specific. The general question is you've been having a lot of regulatory interactions now as you're having your programs go into Phase I and II. You've got a lot of different, or I'd call them, orthogonal approaches ongoing, interacting with different groups at the FDA. What -- do you get a sense that with different groups that there's a potential to accelerate some of the programs, oncology, for example, versus vaccines, et cetera? Do you get a sense that some groups are more amendable to an accelerated approach versus others? And what would those be? And then the more specific question is, just on the PCV, what percent of the patients with their resected melanoma and with a high risk of recurrence actually get KEYTRUDA? And then will you be selecting for patients that have sort of a better immune system status, if that's possible?

我只有幾個問題，一個是一般的，一個是具體的。一般的問題是，當您的程序進入第一階段和第二階段時，您現在已經進行了很多監管互動。你有很多不同的，或者我稱之為正交方法，正在進行中，與 FDA 的不同小組進行互動。什麼——你是否感覺到不同的群體有可能加速某些項目，例如腫瘤學與疫苗等？您是否感覺到某些群體比其他群體更容易接受加速方法？那會是什麼？然後更具體的問題是，僅在 PCV 上，有多少百分比的黑色素瘤切除且複發風險高的患者實際上得到了 KEYTRUDA？然後，如果可能的話，您會選擇免疫系統狀態較好的患者嗎？

Thank you for those. I'm just jotting a note, so I don't forget the questions. The -- let me start with your general question on FDA. It is true that we are interacting across 3 very different disease areas. We've got healthy volunteers in the vaccines division. We've got oncology applications and obviously, rare disease applications. We primarily interact with 2 groups at FDA. It's either the division of vaccines, or OTAT, under which falls both the cancer and rare disease indications. On the vaccine side, I think we're in a very fortunate position. Wellington Sun was the director of that division for the past decade, and he's overseeing the approval of every new vaccine in the space in the U.S. for the past 10 years, has actually joined us a few months back. And he's our Head of Regulatory and Strategy for Vaccines. So I think under his leadership, we have a good sense of what is the best way forward to balance the regulatory risk and the development risk, if you will. In terms of OTAT and are some groups different than others at FDA, I think to give FDA credit, their framework of understanding benefit risk is pretty systemically applied across. I think the hard reality is that we're talking about very different indications and very different assessments of safety and risk versus potential benefit. So of course, when you go into healthy kids with a vaccine, it's a very different bar of how you develop it versus going after rare diseases with huge unmet needs and no standard of care or oncology, which we're all familiar with. I think the totality of our indication -- of our interactions with FDA today, I think has been very positive. Numerous pre-IND meetings, discussions on changes in clinical design, patient population, CMC. I think we found a very active partner that has really helped us. We're starting our first steps into Europe. We've been to Europe, both us and our partners, in several countries. But I give FDA a lot of credit as providing really a deep insight and help as we move forward. In terms of PCV and KEYTRUDA, I'm not sure what the actual commercial numbers are for KEYTRUDA. Suffice to say that it's a recognized standard of care. They have a label in this indication. And I think it's hard to argue that KEYTRUDA is, if not the best, one of the best checkpoint inhibitors in the space. And so I think we're on very solid footing. Certainly, the investigators that I talked to out there who are treating these patients are all very familiar and very comfortable with using KEYTRUDA in this indication. Selecting for patients who are more immunocompetent, I wish I had a way to do that. And I'm open to any ideas. I think it's hard to -- we, as a scientific community, have not really yet found a way that can parse out who is likely to respond and who isn't. I think by going early or in the life of a patient with cancer, if you will, before they've been extensively treated after basically getting a surgical resection, I think gives us the best opportunity to immunize a patient whose immune system is as robust as it can be.

謝謝你的那些。我只是在記筆記，所以我不會忘記問題。 - 讓我從你關於 FDA 的一般問題開始。的確，我們正在 3 個截然不同的疾病領域進行互動。我們在疫苗部門有健康的志願者。我們有腫瘤學應用，顯然還有罕見病應用。我們主要與 FDA 的 2 個小組進行互動。它要么是疫苗部門，要么是 OTAT，癌症和罕見疾病適應症都屬於該部門。在疫苗方面，我認為我們處於非常幸運的位置。 Wellington Sun 在過去十年擔任該部門的負責人，過去十年他負責監督美國太空中每一種新疫苗的批准，實際上幾個月前就加入了我們。他是我們的疫苗監管和戰略主管。因此，我認為在他的領導下，我們很清楚什麼是平衡監管風險和發展風險的最佳方式，如果你願意的話。就 OTAT 而言，有些團體與 FDA 的其他團體不同，我認為給予 FDA 信任，他們理解利益風險的框架非常系統地應用。我認為殘酷的現實是我們正在談論非常不同的適應症以及對安全性和風險與潛在利益的非常不同的評估。因此，當然，當你給健康的孩子接種疫苗時，你開發疫苗的方式與追求罕見疾病的方式截然不同，這些疾病有巨大的未滿足需求且沒有我們都熟悉的護理或腫瘤學標準。我認為我們今天與 FDA 互動的總體指示是非常積極的。多次 IND 前會議，討論臨床設計、患者人群、CMC 的變化。我認為我們找到了一個非常積極的合作夥伴，它確實幫助了我們。我們正在開始進入歐洲的第一步。我們和我們的合作夥伴都去過歐洲的幾個國家。但我非常感謝 FDA，因為它在我們前進的過程中提供了真正深刻的見解和幫助。在 PCV 和 KEYTRUDA 方面，我不確定 KEYTRUDA 的實際商業數字是多少。可以說這是公認的護理標準。他們在這個指示中有一個標籤。而且我認為很難說 KEYTRUDA 即使不是最好的，也是該領域最好的檢查點抑製劑之一。所以我認為我們的基礎非常穩固。當然，我與之交談過的正在治療這些患者的研究人員都非常熟悉並且非常願意在這種適應症中使用 KEYTRUDA。選擇免疫能力更強的患者，我希望我有辦法做到這一點。我願意接受任何想法。我認為這很難——作為一個科學界，我們還沒有真正找到一種方法來分析出誰可能會做出反應，誰不會。我認為通過早期或在癌症患者的生命中，如果你願意的話，在他們基本上接受手術切除後接受廣泛治療之前，我認為為我們提供了最好的機會來免疫免疫系統強大的患者因為它可以。

(Operator Instructions) Our next question comes from the line of Alan Carr, Needham.

（操作員說明）我們的下一個問題來自 Alan Carr，Needham。

You've obviously got a pretty sizable pipeline as it is, but you have talked about your ability to expand beyond that. Wondering if you can give us a sense of to what extent you expect it to grow this year and how you might disclose new programs as they move forward. And then also, in terms of spend for 2019, you said that CapEx would go down. I'm wondering if you can give us a sense, is this something that's going to be substantially lower than 2017 levels even?

你顯然已經有了一個相當大的管道，但你已經談到了你擴展的能力。想知道您是否可以讓我們了解您預計它今年會增長到什麼程度，以及您如何在新計劃推進時披露這些計劃。然後，就 2019 年的支出而言，你說資本支出會下降。我想知道你能否給我們一個感覺，這是否會大大低於 2017 年的水平？

Thank you. It's Stéphane. So I'll take the first question and obviously, Lorence will take the finance question. As we've said in the past, we don't disclose the important work that's happening in research as we go and as we build the business. But what we do is have a few quarterly calls or through different model event, we will share any new development candidate. The team is working on all of our modalities to advance new development candidate. And when they'll be ready, we will communicate those to investors and analysts. Lorence?

謝謝。是斯蒂芬。所以我將回答第一個問題，顯然，Lorence 將回答財務問題。正如我們過去所說，我們不會在我們開展業務和建立業務時披露研究中正在進行的重要工作。但我們所做的是每季度召開幾次電話會議或通過不同的模型活動，我們將分享任何新的開發候選人。該團隊正在研究我們所有的方式來推進新的開發候選人。當他們準備好時，我們會將這些傳達給投資者和分析師。洛倫斯？

Thanks, Alan. On our spend for FY '19 and the CapEx question, yes, we're not specifically guiding on CapEx. But what I can say is that when you look at what's driving CapEx down for this year, it's the fact that Norwood is complete and the investment in Norwood, which was substantial and well worth it was what really bridges between 2017 and 2018. And so if you look at the total cash used to purchase property and equipment in 2017, that was $58 million. And again, a big chunk of that, $40-plus million, was Norwood. So I think that gives you a sense for where we're heading without the specificity of that in here.

謝謝，艾倫。關於我們 19 財年的支出和資本支出問題，是的，我們沒有專門指導資本支出。但我能說的是，當你看看是什麼推動了今年的資本支出下降時，事實是諾伍德已經完成，對諾伍德的投資是巨大且值得的，這才是 2017 年和 2018 年之間真正的橋樑。所以如果你看一下 2017 年用於購買財產和設備的現金總額，那就是 5800 萬美元。再一次，其中很大一部分，40 多萬美元，是諾伍德。因此，我認為這可以讓您了解我們的前進方向，而無需在此說明具體情況。

And I'm showing no further questions at this time. I'd like to turn the conference back over to Stéphane for any closing remarks.

我現在沒有進一步提問。我想將會議轉回給 Stéphane 聽取任何閉幕詞。

Well, thank you very much, everybody, for joining us today and for your questions. We look forward to catching up with many of you in the coming weeks. At the latest, I hope to see you on our May 7 Science Day in Boston. Have a nice day. Thank you.

非常感謝大家今天加入我們並提出問題。我們期待在接下來的幾週內與你們中的許多人見面。最遲，我希望能在我們 5 月 7 日在波士頓舉行的科學日上見到您。祝你今天過得愉快。謝謝。

Ladies and gentlemen, thank you for your participation in today's conference. This does conclude the program. You may now disconnect. Everyone, have a great day.

女士們，先生們，感謝你們參加今天的會議。這確實結束了程序。您現在可以斷開連接。大家，祝你有美好的一天。