莫德納 (MRNA) 2019 Q3 法說會逐字稿

Good morning, and welcome to the Moderna's Third Quarter 2019 Conference Call. (Operator Instructions) Please be advised that this call is being recorded. At this time, I'd like to turn the call over to Lavina Talukdar, Head, Investor Relations in Moderna. Please proceed.

早上好，歡迎來到 Moderna 2019 年第三季度電話會議。 （操作員說明）請注意，此通話正在錄音中。此時，我想將電話轉給 Moderna 投資者關係主管 Lavina Talukdar。請繼續。

Thank you, operator. Good morning, and welcome to Moderna's Third Quarter 2019 Conference Call to discuss business updates and financial results. You can access the press release issued this morning as well as the slides that we'll be reviewing by going to the Investors section of our website.

謝謝你，運營商。早上好，歡迎參加 Moderna 2019 年第三季度電話會議，討論業務更新和財務業績。您可以訪問我們網站的“投資者”部分，訪問今天上午發布的新聞稿以及我們將要審查的幻燈片。

Today on this call, we have Stéphane Bancel, our Chief Executive Officer; Tal Zaks, our Chief Medical Officer; Stephen Hoge, our President; and Lorence Kim, our Chief Financial Officer.

今天在這個電話會議上，我們有我們的首席執行官 Stéphane Bancel；我們的首席醫療官 Tal Zaks；我們的總裁 Stephen Hoge；和我們的首席財務官 Lorence Kim。

Before we begin, I would like to remind everyone that this conference call will include forward-looking statements. Please see Slide 2 of the accompanying presentation and our SEC filings for 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 developments or updates.

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。請參閱隨附演示文稿的幻燈片 2 和我們向美國證券交易委員會提交的文件，了解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的重要風險因素。我們不承擔因新信息或未來發展或更新而更新或修改本次電話會議上提供的信息的義務。

I will now turn the call over to Stéphane.

我現在將把電話轉給 Stéphane。

Thank you, Lavina, and good morning, everyone.

謝謝拉維娜，大家早上好。

We are committed to building mRNA as a new class of medicines, with Moderna positioned to remain the leader in the field. As you know, we believe that mRNA medicines has a potential to help patients by addressing large unmet medical needs and treating diseases that are not addressable by recombinant proteins or small molecules. Through the platform nature of mRNA, we believe mRNA medicines provide a higher probability of technical success and faster time lines to clinical trials compared to traditional medicine. We also believe that the manufacturing capacity intensity of mRNA is materially lower than recombinant protein, and the cost of manufacturing at commercial scale will be similar to small molecule injectables. We continue to focus on managing risk across the portfolio, especially technology and biology risk. In the quarter, we were proud to share positive Phase I data for 2 important milestones of CMV vaccine and our antibody against the chikungunya virus-delivered IV. We show that we successfully immunized seronegative subjects with CMV and boosted seropositives. We plan to start a Phase II study very soon. The GMP material has already been made, and the study protocol has been submitted to the FDA. As a frame of interim results of our Phase II trial, we should be able to make a decision for Phase III dose. The team is already spending a lot of energy to plan for a Phase III study. We believe our CMV vaccine could, if approved, change the future of thousands of children around the world by preventing birth defects. Moderna owns the global commercial rights to the CMV vaccine.

我們致力於將 mRNA 打造成一類新的藥物，而 Moderna 將繼續保持該領域的領先地位。如您所知，我們相信 mRNA 藥物有可能通過解決大量未滿足的醫療需求和治療重組蛋白或小分子無法解決的疾病來幫助患者。通過 mRNA 的平台性質，我們相信與傳統藥物相比，mRNA 藥物提供更高的技術成功概率和更快的臨床試驗時間線。我們還認為，mRNA 的製造能力強度大大低於重組蛋白，商業規模的製造成本將與小分子注射劑相似。我們繼續專注於管理整個投資組合的風險，尤其是技術和生物學風險。在本季度，我們很自豪地分享了 CMV 疫苗和我們針對基孔肯雅病毒 IV 抗體的兩個重要里程碑的 I 期陽性數據。我們表明，我們成功地用 CMV 免疫了血清反應陰性的受試者並增強了血清反應陽性。我們計劃很快開始 II 期研究。 GMP材料已經製作完成，研究方案已經提交給FDA。作為我們 II 期試驗中期結果的框架，我們應該能夠決定 III 期劑量。該團隊已經花費了大量精力來計劃 III 期研究。我們相信，如果獲得批准，我們的 CMV 疫苗可以通過預防出生缺陷來改變全世界成千上萬兒童的未來。 Moderna 擁有 CMV 疫苗的全球商業權利。

We also presented data from the first-ever mRNA-encoded antibody in a human study. We are very proud of this major scientific achievement, and we are eager to move forward with the MMA and PA clinical studies soon. Both of these various programs use the same delivery technology as the one in the antibody program.

我們還展示了人類研究中第一個 mRNA 編碼抗體的數據。我們為這一重大科學成就感到非常自豪，我們渴望盡快推進 MMA 和 PA 臨床研究。這兩個不同的項目都使用與抗體項目相同的遞送技術。

If we step back and look at the body of clinical data over the last 3.5 years, we have come a long way. We started 16 Phase I trials. We dose and maintained 1,400 subjects and patients. We repeat dose up to 8 doses of mRNA up to 3 weeks apart in our OX40 ligand and PCV trials. Additionally, across the 5 modalities for which we have human data, we have consistently shown that our mRNA medicines are well tolerated, results in consistent protein expression in humans, encode for protein that are functional in humans and translate from preclinical models into humans. These findings are very important. They assure that our technology investments are paying off. We believe we are at an important inflection point in the company's history. 5 out of the first 5 modalities have found success in the clinic. That was not easy. Nor was it obvious that it would be the case. Two critical factors explained it for me: one, the quality of our science; two, the quality of our CMC, including manufacturing, technical development and quality. One of my mentors at Eli Lilly, the late Dr. Gus Watanabe, who was President of Lilly Research Labs once told me, "Stéphane, it takes great science to make important medicines. With okay science, well, good luck." We are very humbled to be named for the fifth year in a row among the best employers around the world by Science. To be a Science 2019 top employers speaks loudly of a culture we have established in our scientific teams, among the platform are drug discovery and also process development in manufacturing. We are more than ever committed to be the best mRNA company in the world. It requires the right culture. And being named to this list 5 years in a row by our Moderna colleagues seems to signal we are on the right path. mRNA science is not easy. It requires great collaboration from many disciplines with the right capabilities around the table. We think that with more than 300 scientific colleagues, we have scale. We believe it is very hard to do great mRNA science with a much smaller team.

如果我們退後一步，看看過去 3.5 年的臨床數據，我們已經取得了長足的進步。我們開始了 16 項 I 期試驗。我們對 1,400 名受試者和患者進行給藥和維持。在我們的 OX40 配體和 PCV 試驗中，我們重複給藥多達 8 劑 mRNA，最多間隔 3 週。此外，在我們擁有人類數據的 5 種模式中，我們一直表明我們的 mRNA 藥物具有良好的耐受性，在人類中產生一致的蛋白質表達，編碼對人類有功能的蛋白質，並從臨床前模型轉化為人類。這些發現非常重要。他們確保我們的技術投資得到回報。我們相信我們正處於公司歷史上的一個重要轉折點。前 5 種方式中有 5 種在臨床上取得了成功。這並不容易。也不是很明顯會是這種情況。兩個關鍵因素為我解釋了這一點：一，我們科學的質量；二、我們CMC的質量，包括製造、技術開發和質量。我在禮來公司的一位導師，已故的禮來研究實驗室總裁 Gus Watanabe 博士曾經告訴我，“Stéphane，製造重要的藥物需要偉大的科學。有了好的科學，祝你好運。”我們非常榮幸地連續第五年被 Science 評為全球最佳雇主。 To be a Science 2019 頂級雇主大聲談論我們在科學團隊中建立的文化，其中包括藥物發現和製造過程開發。我們比以往任何時候都更加致力於成為世界上最好的 mRNA 公司。它需要正確的文化。連續 5 年被我們的 Moderna 同事列入這份名單似乎表明我們走在正確的道路上。 mRNA 科學並不容易。它需要來自許多學科的良好協作，並具有合適的能力。我們認為擁有 300 多名科學同事，我們就有了規模。我們相信用一個小得多的團隊很難做偉大的 mRNA 科學。

We, of course, also recognize that great science is being done outside of our walls. As such, a key part of our strategy is to collaborate on research with leading academic and medical centers around the world. We have, over the years, established over 15 collaborations. Our more recent research collaboration with Harvard is centered around developing new medicines for immunonological diseases.

當然，我們也認識到偉大的科學正在我們的牆外進行。因此，我們戰略的一個關鍵部分是與全球領先的學術和醫療中心合作開展研究。多年來，我們已經建立了超過 15 項合作。我們最近與哈佛大學的研究合作集中在開發治療免疫疾病的新藥上。

On Slide 9, you see our current European pipeline. Three important milestones in Q3 to note. The PCV Phase I randomized trial has begun. We reported positive CMV Phase I data. We reported positive result from our antibody program. The first subject has been dosed in the age de-escalation cohort of a Phase Ib of the hMPV+PIV3 vaccine. Zika received fast track designation by the FDA, PA has an open IND by the FDA and recently got fast track designation as well.

在幻燈片 9 上，您可以看到我們當前的歐洲管道。第三季度需要注意的三個重要里程碑。 PCV I 期隨機試驗已經開始。我們報告了積極的 CMV 第一階段數據。我們報告了抗體項目的積極結果。第一個受試者已在 hMPV+PIV3 疫苗的 Ib 期年齡遞減隊列中接種。 Zika 獲得了 FDA 的快速通道指定，PA 擁有 FDA 的開放 IND，最近也獲得了快速通道指定。

Let me now turn to Tal to review our clinical progress.

現在讓我請 Tal 回顧一下我們的臨床進展。

Thank you, Stéphane .

謝謝你，史蒂芬。

We're advancing our pipeline of medicines in 6 different modalities. So let me start with the prophylactic vaccines, where we have treated over 1,000 healthy volunteers across 7 programs to-date. We're pleased with the emerging consistent safety and tolerability profile, and of course, with the repeated demonstration of peptide immunogenicity, which we had expected based both on the fundamentals of expressing of arlant and using our body's own cells and the wealth of preclinical data that continues to translate well in the clinic. The CMV Phase I success is the latest addition here. These data have exceeded our expectations. But before I review them, let me first briefly update you on other progress.

我們正在以 6 種不同的方式推進我們的藥物管道。那麼讓我從預防性疫苗開始，迄今為止，我們已經在 7 個項目中治療了 1,000 多名健康志願者。我們對新出現的一致的安全性和耐受性概況感到滿意，當然，我們對肽免疫原性的反复證明感到滿意，這是我們基於表達 arlant 和使用我們身體自身細胞的基本原理以及大量臨床前數據所預期的這在臨床上繼續得到很好的轉化。 CMV 第一階段的成功是這裡的最新補充。這些數據超出了我們的預期。但在我回顧它們之前，讓我先簡要介紹一下其他進展。

Both the RSV and Zika programs continued to dose patients in their respective Phase I studies. For Zika, we also presented preclinical data at the International Society for Vaccines conference in late October, where vaccination with mRNA-1893 was shown to be fully protective at the lowest dose tested. On the hMPV+PIV3 program, I'm pleased to report that the age de-escalation study as Stéphane noted has started with the first subject dosed. We also presented 7-month immunogenicity data at Infectious Disease Week in October. And finally, with our chikungunya vaccine program, we continued to see good durability with 78.6% of the subjects seropositive to chikungunya virus at 12 months post vaccination.

RSV 和 Zika 項目都在各自的 I 期研究中繼續對患者進行給藥。對於寨卡病毒，我們還在 10 月下旬的國際疫苗學會會議上展示了臨床前數據，在會上，mRNA-1893 疫苗接種在最低測試劑量下顯示出充分的保護作用。在 hMPV+PIV3 計劃中，我很高興地報告，正如 Stéphane 指出的那樣，年齡遞減研究已經從第一個受試者給藥開始。我們還在 10 月份的傳染病週上展示了 7 個月的免疫原性數據。最後，通過我們的基孔肯雅疫苗計劃，我們繼續看到良好的持久性，在接種疫苗後 12 個月時，78.6% 的受試者對基孔肯雅病毒呈血清反應陽性。

So let's get back to CMV.

那麼讓我們回到CMV。

CMV is a common pathogen that is a member of the herpes family of viruses. And like other herpes viruses, it's a lengthened virus, which means once we're infected, it's for life. The largest one associated with CMV is birth defects and disease in babies born to mothers who are infected during pregnancy. The burden of disease is significant, with approximately 25,000 newborns infected each year and is infected each year in the U.S. Currently, there aren't any vaccines against CMV on the market despite repeated attempts over the last 50 years. Now we believe that a reason for prior failures has been the inadequate immunization against the pentameric complex, which the virus uses to infect epithelial cells, either the cells that line body surfaces, and so are the first port of entry for the virus. This pentamer is made of 5 distinct proteins that have to assemble inside the cell before they are transported to the membrane. So trying to make this structure of one protein at a time using traditional recombinant technologies is obviously challenging. However, this challenge can be overcome with our mRNA-based vaccine because our technology enables a simultaneous translation of 5 components.

CMV 是一種常見的病原體，屬於皰疹病毒家族。和其他皰疹病毒一樣，它是一種延長的病毒，這意味著一旦我們被感染，它就是終生的。與 CMV 相關的最大的一個是在懷孕期間被感染的母親所生嬰兒的先天缺陷和疾病。疾病負擔很重，每年大約有 25,000 名新生兒被感染，並且在美國每年都有人感染。儘管過去 50 年來反复嘗試，但目前市場上還沒有任何針對 CMV 的疫苗。現在我們認為，先前失敗的一個原因是針對五聚體複合物的免疫力不足，病毒利用五聚體複合物感染上皮細胞，即排列在體表的細胞，因此是病毒的第一個入口。這種五聚體由 5 種不同的蛋白質組成，這些蛋白質在被輸送到細胞膜之前必須在細胞內組裝。因此，嘗試使用傳統的重組技術一次製造一種蛋白質的這種結構顯然具有挑戰性。然而，我們基於 mRNA 的疫苗可以克服這一挑戰，因為我們的技術可以同時翻譯 5 種成分。

As shown on the bottom half of this slide, mRNA-1647 actually contains 6 mRNA sequences, 5 of which encode for this pentamer and 1 that encodes for gB. Now gB is a relatively simple single-protein receptor. And the important thing is that prior studies with the recombinant vaccine that only included gB already showed prevention of half the cases of CMV infection, which provides us with a very good starting point for demonstrating efficacy.

如本幻燈片的下半部分所示，mRNA-1647 實際上包含 6 個 mRNA 序列，其中 5 個編碼此五聚體，1 個編碼 gB。現在gB是一個比較簡單的單蛋白受體。重要的是，先前對僅包含 gB 的重組疫苗的研究已經表明可以預防一半的 CMV 感染病例，這為我們提供了一個非常好的起點來證明療效。

So let me frame the next 2 data slides.

因此，讓我構建接下來的 2 個數據幻燈片。

Every one of us has either been infected with CMV in the past or not. And if we have, we're lifelong carriers, and our immune system is constantly fighting this chronic infection. So we have antibodies in the serum of our blood, and that is called seropositive. If we've never been infected, we're seronegative. Now both seropositive and seronegative subjects were enrolled in our Phase I study. So we'll be looking at the levels of neutralizing antibody titers for each. mRNA-1647 encodes for the 2 antigen, the pentamer and the gB, that in general, mediate the ability of the virus to infect 2 different cell types, the epithelial cells and fibroblasts. So we will look at titers in the blood of subject that can neutralize the virus' ability to infect either type of cell. And it is important because we're talking about a functional readout. So all in all, we are looking at 4 data set from this trial.

我們每個人過去都感染過或未感染過 CMV。如果有，我們就是終生攜帶者，我們的免疫系統一直在與這種慢性感染作鬥爭。所以我們血液的血清中有抗體，這被稱為血清陽性。如果我們從未被感染，我們就是血清陰性的。現在，血清反應陽性和血清反應陰性的受試者都被納入了我們的第一階段研究。因此，我們將研究每種抗體的中和抗體滴度水平。 mRNA-1647 編碼 2 種抗原，即五聚體和 gB，它們通常介導病毒感染兩種不同細胞類型（上皮細胞和成纖維細胞）的能力。因此，我們將研究受試者血液中可以中和病毒感染任何一種細胞的能力的滴度。這很重要，因為我們正在談論功能讀數。所以總而言之，我們正在查看來自該試驗的 4 個數據集。

Let's start with the seronegative subjects on Slide 13. The top half of the table shows neutralizing antibody titers against epithelial cell infection. I'm going to draw your attention to 2 rows in the top half of the table. The fourth row down labeled GMT post second vaccination, where you will see the titer levels for placebo in each dose tested, which were basically 0 for the placebo group and roughly 3,000 -- 15,000 and 31,000 for the 30-, 90- and 180-microgram dose levels.

讓我們從幻燈片 13 上的血清陰性受試者開始。表格的上半部分顯示了針對上皮細胞感染的中和抗體滴度。我將提請您注意表格上半部分的兩行。向下第四行標記為 GMT post second vaccination，您將在其中看到每個測試劑量中安慰劑的效價水平，安慰劑組基本上為 0，而 30-、90- 和 180- 大約為 3,000 - 15,000 和 31,000微克劑量水平。

The second row to focus on is the sixth row that shows the CMV seropositive titer level of 5,588. This is the level of neutralizing titers seen in the people who have been previously infected by CMV, the seropositives. The row right above shows the ratio between the neutralizing antibody levels achieved with our vaccine relative to that level seen from seropositive subjects in the trial. At the 90- and 180-microgram doses, mRNA-1647 elicited an immune response against epithelial cell infection that is 2.7- and 5.5-fold higher than what is seen in seropositive subjects with natural infection. The reason why this is an important point is that because of the CMV seropositive pregnant women have been observed to have a lower rate of CMV transmission to their unborn children. So these results are striking, and that previous vaccines have not exceeded seropositive levels, and it demonstrates the strong immunological potency of our mRNA vaccine platform.

第二行是第六行，顯示 CMV 血清陽性滴度水平為 5,588。這是在以前感染過 CMV 的人中看到的中和效價水平，即血清陽性。右上一行顯示了我們的疫苗達到的中和抗體水平與試驗中血清陽性受試者的水平之間的比率。在 90 和 180 微克的劑量下，mRNA-1647 引發了針對上皮細胞感染的免疫反應，比自然感染的血清陽性受試者高出 2.7 和 5.5 倍。這一點之所以重要，是因為觀察到 CMV 血清反應陽性的孕婦將 CMV 傳播給未出生的孩子的機率較低。所以這些結果是驚人的，之前的疫苗都沒有超過血清陽性水平，這證明了我們的 mRNA 疫苗平台強大的免疫效力。

The bottom half of the table shows a similar comparison for neutralizing antibody titers against fibroblast. Here, we see our vaccine-induced neutralizing antibody titer levels similar to levels in seropositive subjects. So we've achieved the goal here as well.

表格的下半部分顯示了針對成纖維細胞的中和抗體滴度的類似比較。在這裡，我們看到我們的疫苗誘導的中和抗體滴度水平與血清反應陽性受試者的水平相似。所以我們在這裡也實現了目標。

Taken together, these interim data shows that mRNA-1647 effectively immunizes seronegative subjects to level at/or well above seropositive individuals.

綜上所述，這些中期數據表明，mRNA-1647 可有效地免疫血清反應陰性受試者，使其達到/或遠高於血清反應陽性個體的水平。

Slide 14 shows the same representation of the data, only this time for the seropositive subjects in the trial. Here, placebo subjects started off with neutralizing antibody titers. The average level with, as I described, was 5,588. After both the first and second vaccination, we see marked increases in neutralizing antibody titers. So both vaccinations boost the neutralizing antibody levels well above the baseline. And this is true for epithelial cells as well as fibroblast. With epithelial cells, we see a 10- to 19-fold increase above the CMV-seropositive benchmark. And with fibroblast, we see a 2- to 4-fold increase. It's worth noting that this boosting of seropositive individuals has not been observed with prior vaccines.

幻燈片 14 顯示了相同的數據表示，只是這次是針對試驗中的血清陽性受試者。在這裡，安慰劑受試者從中和抗體滴度開始。正如我所描述的，平均水平是 5,588。在第一次和第二次疫苗接種後，我們看到中和抗體滴度顯著增加。因此，這兩種疫苗接種都能將中和抗體水平提高到遠高於基線的水平。上皮細胞和成纖維細胞都是如此。對於上皮細胞，我們看到比 CMV 血清陽性基準增加了 10 到 19 倍。對於成纖維細胞，我們看到增加了 2 到 4 倍。值得注意的是，以前的疫苗並未觀察到這种血清反應陽性個體的增強作用。

In terms of safety and tolerability, the vaccine was generally safe and well tolerated, with no serious adverse events. Local adverse events included pain, redness and swelling at the injection site. And the most common systemic adverse events were flu-like symptoms of fatigue, fever, chills and myalgia. The adverse events seem to be more common and tend to be more severe in seropositive subjects and after more than one vaccination. In other words, they tend to correlate with the potency of this vaccine to elicit a specific immune response. That said, the adverse events are of a type that one expects to see in a healthy volunteer vaccine trial and are consistent with the safety and tolerability profile that we've seen in our other vaccine trials.

在安全性和耐受性方面，該疫苗總體安全、耐受性好，未發生嚴重不良事件。局部不良事件包括注射部位疼痛、發紅和腫脹。最常見的全身不良事件是疲勞、發燒、發冷和肌痛等流感樣症狀。不良事件似乎更常見，並且在血清反應陽性受試者中和接種不止一次疫苗後往往更嚴重。換句話說，它們往往與這種疫苗引發特定免疫反應的效力相關。也就是說，不良事件是人們期望在健康的志願者疫苗試驗中看到的一種類型，並且與我們在其他疫苗試驗中看到的安全性和耐受性情況一致。

As a reminder, the data I've described thus far, the interim data as analyzed one month after the second dose. Our regimen is a 3-dose regimen at 0, 2 and 6 months. And on this slide, you can see preliminary results from a small cohort of seronegative subjects for which we have data out to a year, following the 3-dose regimen. The solid gray line is the level of seropositive-neutralizing titers against epithelial cell infection. And you can see that everyone starts at 0, gets to the level I previously described by month 3 and are further boosted at month 6, so that they remain at/or above the level of seropositive at least out to a year, with a relatively shallow decline over time. My expectation is that this durability is a function of eliciting strong T cell help, which we know is an inherent feature of our mRNA vaccine platform.

提醒一下，我到目前為止所描述的數據是第二次給藥一個月後分析的中期數據。我們的方案是在 0、2 和 6 個月時分 3 劑給藥。在這張幻燈片上，您可以看到一小群血清陰性受試者的初步結果，我們有這些受試者一年的數據，遵循 3 劑方案。灰色實線是針對上皮細胞感染的血清陽性中和效價水平。你可以看到每個人都從 0 開始，到第 3 個月達到我之前描述的水平，並在第 6 個月進一步提高，因此他們至少在一年內保持在/或高於血清陽性水平，相對隨著時間的推移淺下降。我的期望是這種持久性是引發強大 T 細胞幫助的功能，我們知道這是我們的 mRNA 疫苗平台的固有特徵。

So in summary, we're very pleased with these CMV data. We've shown seronegative subjects who were successfully immunized to generate neutralizing titers, while seropositive subjects were boosted to level above their baseline, something that I don't believe the vaccine community has seen before. mRNA-1647 was generally safe and well tolerated, and we have early evidence of durability out to a year. We're excited by these results and are quickly moving to start a Phase II dose confirmation study. Phase III preparations are well underway. And importantly, FDA feedback suggests a regulatory path to approval using prevention of primary infection in a population that would include women of childbearing age as a basis for licensure, as opposed to a licensure that would be based only on demonstrating the prevention of infection in newborns. We believe a Phase III trial with this endpoint is achievable with less than 8,000 subjects.

所以總而言之，我們對這些 CMV 數據非常滿意。我們已經展示了成功免疫的血清反應陰性受試者產生中和效價，而血清反應陽性受試者被提升到高於其基線的水平，我認為疫苗界以前從未見過這種情況。 mRNA-1647 總體上是安全且耐受性良好的，而且我們有早期證據表明它的耐用性長達一年。我們對這些結果感到興奮，並迅速著手開始 II 期劑量確認研究。三期準備工作正在有條不紊地進行中。重要的是，FDA 的反饋建議通過監管途徑批准在人群中預防原發性感染，其中包括育齡婦女作為許可的基礎，而不是僅基於證明新生兒感染預防的許可.我們相信用不到 8,000 名受試者就可以實現具有此終點的 III 期試驗。

Prevention of CMV in women of childbearing age is a very significant unmet need, which we expect will translate into a large commercial opportunity. Currently, there aren't any vaccines on the market for CMV. And we're targeting a highly motivated population, with clear opportunities down the road for label expansion. The sales effort should be focused, calling on OB/GYNs and pediatricians and assuming pricing similar to other innovative vaccines, one can quickly get to a multibillion-dollar annual sales potential.

在育齡婦女中預防 CMV 是一個非常重要的未滿足需求，我們預計這將轉化為巨大的商業機會。目前，市場上沒有任何針對 CMV 的疫苗。我們的目標人群是積極性高的人群，在標籤擴張的道路上有明顯的機會。銷售工作應重點關注，拜訪婦產科醫生和兒科醫生，並假設定價與其他創新疫苗相似，可以很快達到數十億美元的年銷售潛力。

Moving to the cancer vaccines modality.

轉向癌症疫苗方式。

Recall that both we and NCI demonstrated at ASCO the ability of our personalized cancer vaccine to induce T cells against the new antigens that we encode. The NCI has now completed enrollment of 5 subjects in their trial. They used our personalized cancer vaccine as a single agent in an attempt to further boost the expansion of tumor-infiltrating lymphocytes that they had given to a heavily pretreated patient population. They have not seen any responses to the vaccine as a single agent in these 5 patients.

回想一下，我們和 NCI 在 ASCO 上都展示了我們的個性化癌症疫苗誘導 T 細胞對抗我們編碼的新抗原的能力。 NCI 現在已經完成了 5 名受試者的試驗招募。他們使用我們的個性化癌症疫苗作為單一藥物，試圖進一步促進他們給予經過大量預處理的患者群體的腫瘤浸潤淋巴細胞的擴增。他們沒有看到這 5 名患者對疫苗作為單一藥物有任何反應。

In contrast, our PCV program is designed primarily towards testing the ability of a personalized cancer vaccine to work in synergy with a PD-1 inhibitor and in earlier stages of disease. And to that end, we're actively enrolling patients with melanoma in the randomized Phase II trial, where we will compare our personalized cancer vaccine in combination with KEYTRUDA, versus KEYTRUDA alone for the treatment of patients in the adjuvant setting. The Phase I PCV trial also continues to enroll. And finally, KRAS as a target is getting a lot of attention these days. And our approach is to use the 4 most prevalent KRAS mutations as a cancer vaccine. The trial for our cancer -- for our KRAS vaccine in combination with KEYTRUDA is being run by our partner, Merck. And the Phase I targeting pancreatic, colorectal and lung cancer is ongoing.

相比之下，我們的 PCV 計劃主要旨在測試個性化癌症疫苗與 PD-1 抑製劑協同作用以及在疾病早期階段發揮作用的能力。為此，我們正在積極招募黑色素瘤患者參加隨機 II 期試驗，在該試驗中，我們將比較我們的個性化癌症疫苗與 KEYTRUDA 聯合使用與 KEYTRUDA 單獨用於輔助治療患者的效果。 I 期 PCV 試驗也繼續招募。最後，KRAS 作為目標最近受到了很多關注。我們的方法是使用 4 種最普遍的 KRAS 突變作為癌症疫苗。我們的癌症試驗——我們的 KRAS 疫苗與 KEYTRUDA 的聯合試驗正在由我們的合作夥伴默克公司進行。針對胰腺癌、結直腸癌和肺癌的 I 期臨床試驗正在進行中。

Moving to the intra-tumoral modality.

轉向腫瘤內模式。

We have 3 programs in this sphere, with OX40 ligand, the Triplet and interleukin 12.

我們在這個領域有 3 個項目，包括 OX40 配體、Triplet 和白細胞介素 12。

Starting with mRNA-2416, which encodes OX40 ligand, a potent co-stimulator of immune activation. The Phase I is completing the monotherapy arm and currently dosing patients with a combination of OX40 ligand and durvalumab. We're no longer moving forward with just monotherapy of OX40 ligand, but we'll focus our efforts on the combination with durvalumab, which we intend to move into a Phase II cohort in patients with advanced ovarian cancer once the dose escalation and confirmation cohort is complete. The Phase I trial for mRNA-2752, which encodes for OX40 ligand and 2 pro-inflammatory cytokines, IL-23 and IL-36, is ongoing. We intend to test the combination of this triplet with durvalumab in several tumor-specific cohorts.

從編碼 OX40 配體的 mRNA-2416 開始，OX40 配體是一種有效的免疫激活共刺激劑。 I 期正在完成單一治療組，目前正在給患者服用 OX40 配體和 durvalumab 的組合。我們不再僅採用 OX40 配體的單一療法，而是將我們的努力集中在與 durvalumab 的聯合治療上，我們打算在劑量遞增和確認隊列後進入晚期卵巢癌患者的 II 期隊列做完了。編碼 OX40 配體和 2 種促炎細胞因子 IL-23 和 IL-36 的 mRNA-2752 的 I 期試驗正在進行中。我們打算在幾個腫瘤特異性隊列中測試該三聯體與 durvalumab 的組合。

Finally, our IL-12 program partnered with AstraZeneca based on a similar rationale is also ongoing.

最後，我們基於類似理由與阿斯利康合作的 IL-12 項目也在進行中。

In our localized regenerative modality, the Phase II VEGF trial is ongoing. Recall that our partner, AstraZeneca, has opened additional sites in Europe with the goal of increasing enrollment here.

在我們的局部再生模式中，正在進行 II 期 VEGF 試驗。回想一下，我們的合作夥伴 AstraZeneca 已經在歐洲開設了更多站點，目標是增加這裡的註冊人數。

So let me spend the last few minutes on our systemic therapeutics, starting with recent data we shared at the R&D Day.

因此，讓我用最後幾分鐘來談談我們的系統療法，從我們在研發日分享的最新數據開始。

As a reminder, mRNA-1944 encodes for an antibody against chikungunya virus. Antibodies are complex proteins, consisting both of a heavy and a light chain that come together. So mRNA-1944 includes 2 mRNAs: one that encodes for the heavy chain and one that encodes for the light chain. Once formed, we would expect the antibody to be secreted in the bloodstream where we can measure it.

提醒一下，mRNA-1944 編碼一種針對基孔肯雅病毒的抗體。抗體是複雜的蛋白質，由重鍊和輕鏈組成。所以 mRNA-1944 包括 2 個 mRNA：一個編碼重鏈，一個編碼輕鏈。一旦形成，我們預計抗體會分泌到我們可以測量的血液中。

So here are the Phase I data. We saw a translation of CHKV-24, the antibody in a dose-dependent manner, meaning the more mRNA-1944 you gave, the more CHKV-24 antibody was made. Administering mRNA-1944 at the middle and high doses show protein production well in excess of the 1 microgram per ml level that we had pre-specified as the level predicted to be protective against the chikungunya virus. And the half-life behavior of the protein is exactly as predicted such that the amount of antibody is expected to stay above the 1 microgram level for at least 4 months at the 0.3 mg per kg dose.

所以這是第一階段的數據。我們看到了 CHKV-24 的翻譯，這種抗體呈劑量依賴性，這意味著你提供的 mRNA-1944 越多，產生的 CHKV-24 抗體就越多。以中等和高劑量施用 mRNA-1944 顯示蛋白質產量遠遠超過我們預先指定的 1 微克/毫升水平，該水平被預測為對基孔肯雅病毒具有保護作用。並且該蛋白質的半衰期行為與預測的完全一致，因此在 0.3 mg/kg 的劑量下，抗體的量預計將保持在 1 微克水平以上至少 4 個月。

As you can see in the inset, protein production starts within hours. This is relevant as we think of using this delivery technology to direct the synthesis of intracellular enzymes in liver cells of children born with rare genetic disease, as is the case in methylmalonic acidemia and propionic acidemia.

正如您在插圖中看到的，蛋白質生產會在數小時內開始。這是相關的，因為我們考慮使用這種傳遞技術來指導出生時患有罕見遺傳病的兒童肝細胞中細胞內酶的合成，例如甲基丙二酸血症和丙酸血症。

The final point to make on this slide is the remarkably low intersubject variability, as measured by the coefficient of variance in the range of 20% to 40%. This is similar to what is seen with recombinant proteins. In other words, our delivery technology can direct protein expression without apparent increase in the variability between subjects, which is important as it relates to our ability to define a dose-response relationship, not just within a given subject, but within the population as a whole. We also show that the antibody made using mRNA-1944 is active as expected. Here, the antibody is collected from the serum of subjects and tested against virus in an assay. And it is shown here, as the proportion of patients in whom you can dilute the blood at least a hundredfold and still be able to neutralize the virus.

這張幻燈片的最後一點是主體間變異性非常低，這是通過 20% 到 40% 範圍內的方差係數來衡量的。這與重組蛋白所見相似。換句話說，我們的遞送技術可以指導蛋白質表達，而不會明顯增加受試者之間的變異性，這很重要，因為它關係到我們定義劑量反應關係的能力，不僅在給定受試者內，而且在人群中作為所有的。我們還表明，使用 mRNA-1944 製備的抗體具有預期的活性。在這裡，抗體是從受試者的血清中收集的，並在測定中針對病毒進行了測試。它在這裡顯示為可以將血液稀釋至少一百倍並且仍然能夠中和病毒的患者比例。

Let me review the safety information. Based on the preclinical toxicology, we were able to test mRNA-1944 without steroid premedications, though of course, the investigator had the option of using steroids if needed. For the low and middle doses, we could not distinguish a difference between the drug arm and placebo as it relates to safety. And recall that at the middle dose, we reached potentially therapeutic levels of protein. And at the high dose, we started to see infusion-related reactions that are typically associated with lipid nanoparticles, and in fact, with recombinant proteins at large. These were anticipated in the protocol. They occurred within hours of the infusion, were clinically resolved by the time the subject went to sleep or got up in the morning and did not require medical intervention. We did not see any serious adverse events and we did not see changes in liver or kidney function tests.

讓我回顧一下安全信息。基於臨床前毒理學，我們能夠在沒有類固醇術前用藥的情況下測試 mRNA-1944，當然，如果需要，研究人員可以選擇使用類固醇。對於低劑量和中劑量，我們無法區分藥物組和安慰劑組之間的差異，因為它與安全性有關。回想一下，在中劑量時，我們達到了潛在的蛋白質治療水平。在高劑量下，我們開始看到通常與脂質納米顆粒有關的輸注相關反應，事實上，與重組蛋白有關。這些在協議中是預期的。它們在輸注後數小時內發生，在受試者入睡或早上起床時在臨床上得到解決，不需要醫療干預。我們沒有看到任何嚴重的不良事件，也沒有看到肝或腎功能測試的變化。

To understand the performance of our technology, I'd ask our clinical pharmacology team to model the exposure that we would expect in humans based on the preclinical animal model experience. So here in the shaded areas, you can see the 90% confidence intervals for where we would expect human protein levels to fall at each dose level. And the solid dots are the individual clinical data, landing exactly where expected. Our deliberate technology, in other words, translates from preclinical species to human with no loss of potency. And this is important because it increases our confidence in the predicted activity of the 0.2 mg per kg dose level for MMA, our first rare disease program, because it is using the same delivery, lipid nanoparticle.

為了了解我們技術的性能，我會要求我們的臨床藥理學團隊根據臨床前動物模型經驗對我們預期的人類暴露進行建模。因此，在陰影區域，您可以看到 90% 的置信區間，我們預計每個劑量水平下人體蛋白質水平會下降。實心點是個體臨床數據，準確落在預期位置。換句話說，我們精心設計的技術可以從臨床前物種轉化為人類，而不會損失效力。這很重要，因為它增加了我們對 MMA 0.2 mg/kg 劑量水平的預測活動的信心，這是我們的第一個罕見疾病計劃，因為它使用相同的遞送，脂質納米顆粒。

Given that we explicitly did not include steroid premedication in the first part of the study, the question is whether we can add steroids to the 0.6 mg per kg dose and further reduce or completely eliminate the infusion-related reactions that we've seen. So we're continuing to explore the pharmacology of mRNA-1944 at the 0.6 mg per kg dose level and intend to do so with both the inclusion of steroid premedication as well as by splitting the dose and giving 2 doses of 0.3 mg per kg, 1 week apart, without steroids.

鑑於我們在研究的第一部分明確不包括類固醇術前用藥，問題是我們是否可以將類固醇添加到 0.6 mg/kg 的劑量並進一步減少或完全消除我們已經看到的輸液相關反應。因此，我們將繼續探索 mRNA-1944 在 0.6 mg/kg 劑量水平下的藥理學，並打算通過納入類固醇術前用藥以及分開劑量並給予 2 劑 0.3 mg/kg 來做到這一點，間隔 1 週，不使用類固醇。

So I look forward to continuing to show the data as it emerges from this trial.

因此，我期待繼續展示本次試驗中出現的數據。

In summary, we're really happy with the results of our chikungunya antibody program, mRNA-1944. We saw a dose-dependent increase in levels of antibodies against the chikungunya virus. The antibodies were functional, with a predicted translation profile from species to species and no loss of potency when we bring it into humans. mRNA-1944 was also well tolerated in a healthy volunteer population at a dose where we saw therapeutic levels of antibodies being produced. And importantly, these results bode well for our rare disease programs like MMA, that use the same LNP delivery technology as mRNA-1944.

總之，我們對我們的基孔肯雅抗體項目 mRNA-1944 的結果非常滿意。我們看到抗基孔肯雅病毒的抗體水平呈劑量依賴性增加。這些抗體是有功能的，具有從物種到物種的預測翻譯譜，並且當我們將其引入人類時不會喪失效力。 mRNA-1944 在健康志願者群體中的耐受性也很好，我們看到產生了治療水平的抗體。重要的是，這些結果預示著我們的罕見病項目（如 MMA）使用與 mRNA-1944 相同的 LNP 遞送技術。

So this brings me to the intracellular therapeutics. And in this modality, let me provide you a quick update on MMA and PA. These are similar diseases caused by inborn error of protein metabolism and are caused by MUT enzyme deficiency or PCC deficiency, both of which act intracellularly.

所以這讓我想到了細胞內療法。在這種模式下，讓我為您提供有關 MMA 和 PA 的快速更新。這些是由蛋白質代謝的先天性錯誤引起的類似疾病，是由 MUT 酶缺乏或 PCC 缺乏引起的，兩者均在細胞內起作用。

Our MMA and PA programs aim to replace these proteins and bring the protein metabolism and the associated acidemia levels closer to normal. From a regulatory standpoint, mRNA-3704 and mRNA-3927 have similar designations. Both compounds have FDA orphan drug designation, EMA orphan disease status, FDA fast-track status and FDA rare pediatric disease designation, which upon approval, will qualify the 2 programs for rare pediatric disease vouchers. The Phase I study for MMA is currently active recruiting patients, and the PA program recently had its IND open. And we're preparing to start a Phase I/II trial there shortly.

我們的 MMA 和 PA 計劃旨在替代這些蛋白質，並使蛋白質代謝和相關的酸血症水平更接近正常。從監管的角度來看，mRNA-3704 和 mRNA-3927 具有相似的名稱。這兩種化合物都具有 FDA 孤兒藥指定、 EMA 孤兒病狀態、 FDA 快速跟踪狀態和 FDA 罕見兒科疾病指定，一旦獲得批准，這兩個項目將有資格獲得罕見兒科疾病券。 MMA 的 I 期研究目前正在積極招募患者，PA 項目最近也開放了 IND。我們正準備很快在那裡開始 I/II 期試驗。

Now regarding MMA, the initial cohort was limited by FDA to adolescents between the ages of 12 and 18. And during the summer, we had gone back to the agency, and they allowed for the expansion of this age bracket to include patients older than 8. While we're continuing the dialogue with FDA regarding further modification to the enrollment criteria, in the past few weeks, this amended protocol has been approved by the IRBs of the first few institutions. So I look forward to updating you on our progress soon.

現在關於 MMA，最初的隊列被 FDA 限制為 12 到 18 歲之間的青少年。在夏天，我們回到了該機構，他們允許擴大這個年齡段以包括 8 歲以上的患者. 在我們繼續與 FDA 就進一步修改入組標准進行對話的同時，在過去幾週內，這一修訂後的協議已獲得前幾家機構的 IRB 批准。因此，我期待盡快向您通報我們的進展情況。

PA has a similar design and similar initial age restrictions. And following the opening of the IND and subsequent fast track designations, we have begun start-up activities at the leading academic centers.

PA 具有類似的設計和類似的初始年齡限制。隨著 IND 的開放和隨後的快速通道指定，我們已經開始在領先的學術中心開展啟動活動。

Let me close with Slide 32, which lists the anticipated next steps and upcoming clinical catalysts. And I'll focus you on the CMV Phase II start as well as the eventual readout and on the MMA and PA Phase I/II trials.

讓我以幻燈片 32 結束，它列出了預期的後續步驟和即將到來的臨床催化劑。我將重點介紹 CMV II 期的開始以及最終的讀數以及 MMA 和 PA I/II 期試驗。

With that, let me turn the call over to Lorence.

有了這個，讓我把電話轉給洛倫斯。

Thank you, Tal.

謝謝你，塔爾。

In today's press release, we reported our third quarter 2019 financial results. Please note, these results are unaudited.

在今天的新聞稿中，我們公佈了 2019 年第三季度的財務業績。請注意，這些結果未經審計。

We ended Q3 2019 with cash, cash equivalents and investments of $1.34 billion. This compares to $1.69 billion at the end of 2018. Net cash used in operating activities was $363 million for the first 9 months of 2019 compared with $240 million in 2018. And cash used for repurchases of property and equipment was $25 million for the first 9 months of 2019 compared to $92 million in 2018, which was the first year that we put our Norwood manufacturing facility into service.

我們在 2019 年第三季度末擁有 13.4 億美元的現金、現金等價物和投資。相比之下，2018 年底為 16.9 億美元。2019 年前 9 個月用於經營活動的現金淨額為 3.63 億美元，而 2018 年為 2.4 億美元。前 9 個月用於回購財產和設備的現金為 2500 萬美元2019 年為 9200 萬美元，而 2018 年是我們將諾伍德製造工廠投入使用的第一年。

Now recall that on January 1, 2019, we adopted the mandated revenue recognition standard, ASC 606, using the modified retrospective transition method applied to those contracts which were not completed as of January 1, 2019. And so the decreases in total revenue for Q3 and for the first 9 months of 2019 compared to 2018 were mainly attributable to the adoption of this new revenue standard.

現在回想一下，在 2019 年 1 月 1 日，我們採用了強制性收入確認標準 ASC 606，使用適用於截至 2019 年 1 月 1 日尚未完成的合同的修改追溯過渡法。因此，第三季度總收入減少2019 年前 9 個月與 2018 年相比主要是由於採用了這一新收入準則。

Revenue for Q3 2019 was $17 million as compared to $42 million for Q3 of 2018. And for the first 9 months of 2019, revenue was $46 million compared to $100 million in 2018. Total revenue under the previous revenue recognition standard would have been $25 million for Q3 2019 and $80 million for the first 9 months of 2019.

2019 年第三季度的收入為 1700 萬美元，而 2018 年第三季度為 4200 萬美元。2019 年前 9 個月的收入為 4600 萬美元，而 2018 年為 1 億美元。根據之前的收入確認標準，總收入為 2500 萬美元2019 年第三季度和 2019 年前 9 個月的 8000 萬美元。

R&D expenses for Q3 2019 were $120 million compared to $109 million for Q3 2018. For the first 9 months of 2019, R&D expenses were $379 million compared to $304 million in 2018. The increase in Q3 and for the first 9 months of 2019 compared to prior year was mainly driven by an increase in personnel-related costs, including stock-based compensation, with additional increases for the first 9 months of 2019 being driven by higher clinical trial, manufacturing costs and increase in lab supplies and materials, and an increase in consulting and outside services.

2019 年第三季度的研發費用為 1.2 億美元，而 2018 年第三季度為 1.09 億美元。2019 年前 9 個月的研發費用為 3.79 億美元，而 2018 年為 3.04 億美元。與上一年主要是由於與人員相關的成本增加，包括基於股票的補償，2019 年前 9 個月的額外增加是由於臨床試驗、製造成本和實驗室用品和材料的增加，以及增加在諮詢和外部服務方面。

G&A expenses for Q3 2019 were approximately $28 million compared to $19 million in Q3 2018. And for the first 9 months of 2019, G&A expenses were $84 million compared to $56 million in 2018. The increases in Q3 and the first 9 months of 2019 compared to the prior year were mainly due to the additional costs of operating as a publicly traded company, including an increase in personnel-related costs and stock-based compensation, consulting and outside services, legal and insurance costs.

2019 年第三季度的 G&A 費用約為 2800 萬美元，而 2018 年第三季度為 1900 萬美元。2019 年前 9 個月的 G&A 費用為 8400 萬美元，而 2018 年為 5600 萬美元。與 2019 年前 9 個月相比，第三季度和 2019 年前 9 個月的增長與上一年相比，主要是由於作為上市公司運營的額外成本，包括人員相關成本和股票薪酬、諮詢和外部服務、法律和保險成本的增加。

Let me now drill down on our balance sheet strength.

現在讓我深入了解我們的資產負債表實力。

We ended Q3, as I mentioned, with cash, cash equivalents and investments of $1.34 billion. That balance sheet is augmented by our access to a number of grants. We are fortunate to have established strategic alliances with government-sponsored and private organizations, including DARPA, BARDA and the Bill & Melinda Gates Foundation. And so as of September 30, 2019, we've recognized $59 million in revenue to-date, while we have a total additional available funding of $187 million, comprising $99 million of committed funding and another $88 million of non-committed funding that we can tap into.

正如我所提到的，我們在第三季度結束時擁有 13.4 億美元的現金、現金等價物和投資。我們獲得了一些贈款，資產負債表得到了擴充。我們有幸與政府贊助和私人組織建立了戰略聯盟，包括 DARPA、BARDA 和比爾及梅琳達蓋茨基金會。截至 2019 年 9 月 30 日，我們迄今已確認 5900 萬美元的收入，同時我們還有 1.87 億美元的額外可用資金，包括 9900 萬美元的承諾資金和另外 8800 萬美元的非承諾資金。可以點進去。

I'll turn now to where we expect to end 2019.

我現在將轉向我們預計 2019 年結束的地方。

We ended 2018 with $1.69 billion in cash, cash equivalents and investments. And early this year, we guided to a year-end 2019 cash balance of $1.15 billion to $1.20 billion. We've reiterated that guidance on subsequent quarterly calls. And today, we are guiding the year-end cash at the high end of that range. That is, we expect to have approximately $1.2 billion at the end of 2019. This works out to a change in cash of less than $500 million for 2019.

2018 年底，我們擁有 16.9 億美元的現金、現金等價物和投資。今年年初，我們預計 2019 年年底的現金餘額為 11.5 億美元至 12 億美元。我們在隨後的季度電話會議上重申了這一指導意見。而今天，我們將年終現金指導在該範圍的高端。也就是說，我們預計到 2019 年底將有大約 12 億美元。這意味著 2019 年的現金變化不到 5 億美元。

I also want to highlight 2 specific cash flow line items, our cash used in operating activities and purchases of property and equipment by quarter. In Q1, we used $152 million of cash in these 2 items. That number included $22 million of in-licensing payments, but we have no further in-licensing payment obligations to these entities going forward. And then you can see the decline in our quarter-over-quarter cash used for these items and a year-to-date number of $388 million.

我還想強調 2 個具體的現金流項目，即我們在經營活動中使用的現金以及按季度購買的財產和設備。第一季度，我們在這兩個項目上使用了 1.52 億美元的現金。該數字包括 2200 萬美元的許可付款，但我們今後對這些實體沒有進一步的許可付款義務。然後你可以看到我們用於這些項目的現金環比下降，年初至今為 3.88 億美元。

And so when we look ahead to the full year on these cash flow metrics, we can expect 2019 net cash used in operating activities and purchases of property and equipment to total approximately $500 million. As we've said in the past, this reflects our ongoing focus on allocation of our shareholders' capital toward value-driving investments in our portfolio and platform.

因此，當我們根據這些現金流量指標展望全年時，我們可以預計 2019 年用於經營活動和購買財產和設備的淨現金總額約為 5 億美元。正如我們過去所說，這反映了我們持續關注將股東資本分配給我們的投資組合和平台的價值驅動投資。

Lastly, as we look at 2020, we are issuing guidance now for next year around these same cash flow metrics. I'll start by noting that we actually expect the trend to be relatively flat year-over-year. This trend is really due to a combination of factors. First, we had nonrecurring costs, such as the $22 million of in-licensing payments in 2019. Also at this time, with Norwood operating well, our need for significant new facilities and associated capital expenditures is limited. And our pipeline, while it's advancing well, is actually not burdened with very large trials in 2020. For instance, while we are planning for a substantial Phase III CMV vaccine study, that program only requires pre-investment in 2020. And lastly, I'll note that our partners fund significant development costs for programs such as RSV, Zika, KRAS, IL-12, VEGF and chikungunya antibody. And so for these reasons, we do not expect growth in our cash needs for next year, while being able to fund significant pipeline advancement and ongoing platform development.

最後，展望 2020 年，我們現在將圍繞這些相同的現金流量指標發布明年的指導意見。我首先要指出的是，我們實際上預計這一趨勢將同比持平。這種趨勢實際上是多種因素共同作用的結果。首先，我們有非經常性成本，例如 2019 年 2200 萬美元的許可費用。同樣在此時，由於 Norwood 運營良好，我們對重要新設施和相關資本支出的需求有限。我們的管道雖然進展順利，但實際上並沒有在 2020 年進行非常大規模的試驗。例如，雖然我們計劃進行大規模的 III 期 CMV 疫苗研究，但該計劃只需要在 2020 年進行預投資。最後，我您會注意到，我們的合作夥伴為 RSV、寨卡病毒、KRAS、IL-12、VEGF 和基孔肯雅抗體等項目資助了大量開發成本。因此，由於這些原因，我們預計明年的現金需求不會增長，同時能夠為重大的管道推進和持續的平台開發提供資金。

As a result, our guidance is that we expect net cash used in operating activities and for purchases of property and equipment to total $490 million to $510 million for 2020, very similar to where we will end 2019.

因此，我們的指導意見是，我們預計 2020 年用於經營活動和購買財產和設備的淨現金總額將達到 4.9 億至 5.1 億美元，與 2019 年底的情況非常相似。

As I hand it back to Stéphane, I'll close again with our pipeline, which reiterates my last point on the number of programs that we've highlighted that our partner-funded.

當我把它交還給 Stéphane 時，我將再次關閉我們的管道，這重申了我最後一點關於我們強調的由我們的合作夥伴資助的項目數量的觀點。

Stéphane?

斯蒂芬？

Thank you, Lorence.

謝謝你，洛倫斯。

To close, I would like to spend a couple of minutes on the development products and why we are so excited about them and what they can do for patients.

最後，我想花幾分鐘談談開發產品，以及為什麼我們對它們如此興奮以及它們可以為患者做些什麼。

Let's start with our innovative vaccines. We now have in the clinical studies 4 important innovative vaccines: the CMV vaccine, RSV vaccine, a combo hMPV+PIV3 vaccine and the Zika vaccine. There are no approved vaccines to protect humans from these 5 viruses. The morbidity and mortality costs around the world by these 5 viruses is devastating. We believe CMV, RSV and our hMPV+PIV3 combo are each multibillion-dollar annual fixed sales opportunities and Zika is a several hundred million-dollar annual fixed sales opportunity. We know that our vaccine translates well from preclinical models to Phase I data. And it is well documented in the pharmaceutical industry that vaccines, once they show a positive Phase I, have the highest probability to launch across any therapeutic area.

讓我們從我們的創新疫苗開始。我們現在在臨床研究中有 4 種重要的創新疫苗：CMV 疫苗、RSV 疫苗、hMPV+PIV3 組合疫苗和寨卡疫苗。沒有批准的疫苗可以保護人類免受這 5 種病毒的侵害。這 5 種病毒在世界範圍內造成的發病率和死亡率成本是毀滅性的。我們相信 CMV、RSV 和我們的 hMPV+PIV3 組合每年都有數十億美元的固定銷售機會，而 Zika 則是每年數億美元的固定銷售機會。我們知道我們的疫苗可以很好地從臨床前模型轉化為 I 期數據。製藥行業有充分的證據表明，疫苗一旦顯示出陽性 I 期，就最有可能在任何治療領域推出。

We have 5 immuno-oncology programs in the clinic that is a remarkable pipeline. For all of 5 oncology programs, our aim is the same. Can we add an innovative mRNA medicine to a commercial PD-1 or PD-L1 to improve the response rate of these patients? Checkpoints are wonderful medicines, but unfortunately, most patients do not respond to checkpoint inhibitors. We believe there is a large commercial opportunity to improve the complete response rate of checkpoint inhibitors, and we have 5 opportunities to try to do that.

我們在診所有 5 個免疫腫瘤學項目，這是一個了不起的管道。對於所有 5 個腫瘤學項目，我們的目標是相同的。我們能否在商業化的 PD-1 或 PD-L1 中加入一種創新的 mRNA 藥物來提高這些患者的反應率？檢查點是很好的藥物，但不幸的是，大多數患者對檢查點抑製劑沒有反應。我們相信有很大的商業機會來提高檢查點抑製劑的完全反應率，我們有 5 個機會嘗試這樣做。

And finally, in rare diseases. Here too, we have 5 important medicines in development. 3 of these are designed to treat devastating diseases for which there are no approved medicine on the market: MMA, PA, GSD1a; and 2 of them are designed to improve the standard of care for patients for PKU and Fabry.

最後，在罕見病中。在這裡，我們也有 5 種重要的藥物正在開發中。其中 3 種旨在治療市場上沒有批准藥物的破壞性疾病：MMA、PA、GSD1a；其中 2 個旨在提高 PKU 和 Fabry 患者的護理標準。

Our priorities for 2019, 2020. Priority #1 is to execute on our pipeline. I am pleased with the progress across the board in 2019, especially with clinical data, more CMV vaccine and our antibody against chikungunya virus programs, as well as our PCV program now in Phase II. Priority 2 was named new development candidate in our existing modalities. We then have new DC for GSD1a earlier this year. And priority #3 is to create new development candidate in new modalities. We are continuing to make good progress in several new modalities, and we look forward to sharing some updates in 2020.

我們 2019 年和 2020 年的優先事項。第一要務是在我們的管道上執行。我對 2019 年的全面進展感到滿意，尤其是臨床數據、更多 CMV 疫苗和我們的基孔肯雅病毒抗體項目，以及我們目前處於 II 期的 PCV 項目。在我們現有的模式中，優先級 2 被命名為新的開發候選項目。然後，我們在今年早些時候為 GSD1a 提供了新的 DC。第三優先事項是以新模式創建新的開發候選項目。我們在幾種新模式上繼續取得良好進展，我們期待在 2020 年分享一些更新。

In summary, we are pleased with the pace of execution. The key highlights of our third quarter are the positive Phase I data for CMV and the antibody for chikungunya. We have up to $1.5 billion to invest in the business with enough cash, balance and grant. We invest approximately $500 million in our company in 2019 and also approximately $500 million in 2020. We intend to continue to do new partnership with biopharma companies and to apply for new grants.

總之，我們對執行速度感到滿意。我們第三季度的主要亮點是 CMV 和基孔肯雅抗體的陽性 I 期數據。我們有高達 15 億美元的資金用於投資業務，並提供足夠的現金、餘額和贈款。我們在 2019 年向公司投資約 5 億美元，2020 年也投資約 5 億美元。我們打算繼續與生物製藥公司建立新的合作夥伴關係併申請新的贈款。

We know that we have a special opportunity, and we are committed to delivering on the promise of our science and bring forward a new class of medicines for patients. I would like to end our remarks by thanking the many people who participate in our clinical studies, including patients, healthy volunteers and physician. I would also like to thank the great team at Moderna, working hard every day to make this vision a reality.

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，為患者帶來一類新的藥物。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。我還要感謝 Moderna 的優秀團隊，他們每天都在努力工作，使這一願景成為現實。

With that, we are now happy to take any question. 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 with Morgan Stanley.

（操作員說明）我們的第一個問題來自馬修哈里森與摩根士丹利的合作。

Great. Thanks for the detail on the update here. I guess 2 parts for me. So first, could you just talk about the progress in being able to enroll patients in MMA? I think you've had sites opened for a bit of time here and now you've been able to expand the age group, but it doesn't sound like you've enrolled the patients yet. So maybe you can just talk about what's going on there. And then second, on chikungunya, maybe just talk about when we should expect to see some information about dosing profile and if you're able to drive dose higher with premedication or split dosing.

偉大的。感謝您在此處提供有關更新的詳細信息。我想我有 2 個部分。那麼首先，您能否談談在 MMA 招募患者方面取得的進展？我想你們已經在這裡開放了一段時間的網站，現在你們已經能夠擴大年齡組，但聽起來你們還沒有招募患者。所以也許你可以談談那裡發生了什麼。其次，關於基孔肯雅熱，也許只是談談我們應該期望什麼時候看到一些關於劑量分佈的信息，以及你是否能夠通過術前用藥或分次給藥來提高劑量。

Thank you, Matthew. This is Tal. Let me address both of your questions. You're right on MMA. We have not yet dosed our first subject. We, as noted, initially, FDA had requested that we limit the first 3 subject to ages 12 and above, before we can proceed to the children that are young as -- as young as 1 year old where the highest unmet need is. And I think we found in opening the sites and trying to enroll this that there are several factors that come into play. By the time somebody gets to be an adolescent, if their disease has been severe, they've often had a liver transplant. In fact, liver transplants in the U.S. are recommended between the age of a year in preschool. And when a kid with MMA shows up for liver transplant, they move to the top of the queue, so there's not much waiting. Those who don't get a liver transplant often suffer from kidney deterioration, and we can't do a Phase I trial with really abnormal kidney function. So we have gone back in the summer, as noted, to discuss with FDA, lowering the age criteria. They had agreed to take it down to the ages of 8 and above. And while we're still in dialogue with them about that, the amendment to enable us to do that has just recently opened at some of the leading institutions, and I look forward to enrolling the first subject soon. It has been a challenge for all those factors that I alluded to. But I think between lowering the age and now being open at some of the select institutions, we should see progress soon.

謝謝你，馬修。這是塔爾。讓我回答你的兩個問題。你說得對 MMA。我們還沒有給我們的第一個受試者服藥。如前所述，我們最初要求 FDA 將前 3 名受試者的年齡限制在 12 歲及以上，然後我們才能繼續治療最年幼的兒童——年僅 1 歲，其中未滿足的需求最高。我認為我們在打開網站並嘗試註冊時發現有幾個因素在起作用。當某人成為青少年時，如果他們的疾病很嚴重，他們通常會進行肝移植。事實上，美國建議在學齡前一歲之間進行肝臟移植。當一個患有 MMA 的孩子來接受肝臟移植時，他們會排在隊伍的最前面，所以沒有太多的等待時間。那些沒有接受肝移植的人往往會出現腎功能惡化，我們無法在腎功能真正異常的情況下進行 I 期試驗。因此，如前所述，我們在夏天回去與 FDA 討論降低年齡標準。他們同意將其降低到 8 歲及以上。雖然我們仍在與他們就此進行對話，但最近一些領先機構剛剛開始實施修正案，使我們能夠做到這一點，我期待著盡快招收第一個受試者。對於我提到的所有這些因素來說，這一直是一個挑戰。但我認為，在降低年齡和現在在一些特定機構開放之間，我們應該很快就會看到進展。

Now you'd asked me about the chikungunya and when do you expect to see data. This is a healthy volunteer trial. So we had gone back to the safety monitoring committee, aligned with them on the next steps, and we're actively working with the site to get the next cohorts enrolled. So as soon as data will become available and we understand what it is we have, we'll be sharing it with you. Being a healthy volunteer trial, it should move relatively quickly.

現在你問我關於基孔肯雅熱的問題，你希望什麼時候看到數據。這是一項健康的志願者試驗。所以我們回到了安全監督委員會，在接下來的步驟中與他們保持一致，我們正在積極與該網站合作，讓下一批人參與進來。因此，一旦數據可用並且我們了解我們擁有的數據，我們就會與您分享。作為一項健康的志願者試驗，它應該相對較快地進行。

And our next question comes from the line of Ted Tenthoff with Piper Jaffray.

我們的下一個問題來自 Ted Tenthoff 與 Piper Jaffray 的對話。

Great. Thanks for the update and all of the great progress. I want to ask about the CMV vaccine, really just get a little bit better clarity on what you see as the path forward here. Appreciating a Phase II dose confirmation start next year. Can you give us a sense of the size of that study and maybe how long it would take? And then looking kind of forward, how soon do you think you could actually initiate pivotal studies in women of childbearing age?

偉大的。感謝您的更新和所有的巨大進步。我想問一下關於 CMV 疫苗的問題，真的只是更清楚地了解您所看到的前進道路。感謝明年開始 II 期劑量確認。你能告訴我們這項研究的規模以及可能需要多長時間嗎？然後展望未來，您認為您真正開始對育齡婦女進行關鍵研究需要多長時間？

Thank you, Ted. This is Tal. I'll take that question. So a couple of points. First, in terms of size and timing, the Phase II is about 250 subjects or so. The design is really meant to confirm the dose and give us more color on both immunogenicity and safety and tolerability so that we are able to pick the right dose for Phase III. That being said, the time should be relatively quickly because the -- we'll make the decision based on a 3-month endpoint once everybody has been dosed, similar to what the interim data that we've shown in the Phase I. By then, we will have the further follow-up post the third dose in the Phase I, so we'll have overall more data to be able to share and substantiate that decision.

謝謝你，特德。這是塔爾。我會回答這個問題。所以有幾點。首先，就規模和時間而言，第二階段大約有 250 個科目。該設計實際上是為了確認劑量，並為我們提供更多關於免疫原性和安全性和耐受性的顏色，以便我們能夠為 III 期選擇合適的劑量。話雖這麼說，時間應該相對較快，因為——我們將根據每個人都被給藥後的 3 個月終點做出決定，類似於我們在第一階段中顯示的中期數據。然後，我們將在第一階段的第三劑後進行進一步的跟進，因此我們將有更多的數據來分享和證實該決定。

Now the path to Phase III, I think the big change here for me has been the fact that FDA has provided guidance that speaks of the potential for licensure based on the prevention of primary infection. And that's very significant because that means that it is imminently doable with the trial of the size that we've discussed.

現在進入 III 期階段，我認為對我來說最大的變化是 FDA 提供的指導說明了基於預防原發感染的許可潛力。這非常重要，因為這意味著我們已經討論過的規模試驗是迫在眉睫的。

In terms of launching that, I would say the 2 gating factors that I think to actually launching that study are going to be the Phase II data and some regulatory discussions. This was just very preliminary initial guidance, of course, before one launches a Phase III trial here, we'd need to have those more deep discussions with FDA and other agencies to make sure we're launching the right study. Now once we get their agreement, I think the design is fairly straightforward, one would expect an incident rate of about 1.5% a year. So hopefully, with a couple of years of follow-up once everybody is enrolled, you could see the effect that you're looking for and wrap it up. So that gives you a rough sense of the overall time line here.

就啟動而言，我想說我認為實際啟動該研究的兩個門控因素將是 II 期數據和一些監管討論。當然，這只是非常初步的初步指導，在開展 III 期試驗之前，我們需要與 FDA 和其他機構進行更深入的討論，以確保我們開展的研究是正確的。現在一旦我們得到他們的同意，我認為設計相當簡單，預計每年的事故率約為 1.5%。因此，希望在每個人都註冊後進行幾年的跟進，您可以看到您正在尋找的效果並將其總結。這樣您就可以大致了解這裡的總體時間線。

Great. That's super helpful. And then if I may just ask a second question. Appreciating that it's with Merck, when could we get data from the enhanced RSV vaccine?

偉大的。這非常有幫助。然後我可以問第二個問題。感謝默克公司，我們什麼時候可以從增強型 RSV 疫苗中獲得數據？

Yes. That's a great question. I ask it as well. The truth is that they are pretty efficient in running these trials. They've got a long track record of running a healthy volunteer vaccine trials and of analyzing data quickly. So as soon as they have something material to share with us, we'll of course share it with you.

是的。這是一個很好的問題。我也問。事實上，他們在進行這些試驗時非常有效。他們在開展健康的志願者疫苗試驗和快速分析數據方面有著長期的記錄。因此，一旦他們有一些材料要與我們分享，我們當然會與您分享。

And our next question comes from the line of Salveen Richter with Goldman Sachs.

我們的下一個問題來自 Salveen Richter 與高盛的合作。

Maybe a first question here on how your chikungunya vaccine clinical development plan reflects the guidance that was provided by the FDA. And then a second question, on the chikungunya antibody program here. Could you just walk us through your plans for evaluating repeat dosing, recognizing that you do have this cohort study coming up with 2 doses about a week apart?

也許這裡的第一個問題是關於你們的基孔肯雅疫苗臨床開發計劃如何反映 FDA 提供的指南。然後是第二個問題，關於這裡的基孔肯雅抗體項目。您能否向我們介紹一下您評估重複給藥的計劃，並認識到您確實有這項隊列研究提出了間隔大約一周的 2 劑？

Thank you, Salveen. This is Tal. I'll take that. So the plan to develop a chikungunya vaccine is a great question. It's true that FDA is giving a potential path. In fact, there's a big discussion in a couple of days time down at FDA where our team is presenting alongside others to flesh out what that could look like. To-date, it hasn't been clear how one could develop it and do it in a commercially viable setting. To the degree that the discussions with the agency in the near term will actually paint a path where it would be worth our capital and time to go there, we'll obviously be looking at it carefully. So I don't have a clear answer because I think this is a work in progress. To-date, we've not seen a commercial path. I'm happy with the recent agency guidance, and we'll see how the conversations go.

謝謝你，薩爾文。這是塔爾。我會接受的。所以開發基孔肯雅疫苗的計劃是一個很好的問題。 FDA 確實提供了一條潛在路徑。事實上，幾天后在 FDA 進行了一場大討論，我們的團隊將與其他人一起展示，以充實它的外觀。迄今為止，尚不清楚如何開發它並在商業上可行的環境中進行。就近期與該機構的討論實際上描繪出一條值得我們的資金和時間去那裡的道路而言，我們顯然會仔細研究它。所以我沒有明確的答案，因為我認為這是一項正在進行的工作。迄今為止，我們還沒有看到商業路徑。我對最近的機構指南感到滿意，我們將看看對話的進展情況。

Your question on repeat dosing for the monoclonal antibody program. The goal really here is to substantiate our ability to stack pharmacology. In other words, to show that the antibody level, the protein level production of 2 doses given a week apart, behave as expected in the clinic. We have seen that in the preclinical toxicology in the nonhuman primate, but I think being able to show that, and leveraging the fact that the adverse event profile seems to be a very quick infusion-related reactions that come on quickly and come off quickly, we would expect that there would -- there should not be any stacking in terms of safety, while there would be stacking in terms of pharmacology. And that's the rationale of doing 2 doses 1 week apart at a dose where we actually have not seen any significant adverse events. Did that answer the question?

您關於單克隆抗體程序重複給藥的問題。這裡的真正目標是證實我們疊加藥理學的能力。換句話說，為了表明抗體水平，即間隔一周給予 2 劑的蛋白質水平的產生，表現與臨床預期的一樣。我們已經在非人類靈長類動物的臨床前毒理學中看到了這一點，但我認為能夠證明這一點，並利用不良事件概況似乎是一種非常快速的輸液相關反應這一事實，這種反應來得快去得也快，我們預計會有——在安全方面不應該有任何堆疊，而在藥理學方面會有堆疊。這就是間隔 1 週接種 2 劑的基本原理，我們實際上沒有看到任何明顯的不良事件。這回答了問題嗎？

Yes. That was helpful.

是的。那很有幫助。

Thank you.

謝謝。

And our next question comes from the line of Cory Kasimov with JPMorgan.

我們的下一個問題來自摩根大通的 Cory Kasimov。

So 2 as well. So first is just following up on CMV. And as you get the Phase II sites up and running and plan for your Phase III, are there any additional processes or challenges we should be thinking about given the new modality you're introducing? Or is this something that you think you can go pretty quickly from a patient accrual point of view? And then my second question is just regarding your natural history studies for MMA and PA. What's the age range you have there for the natural history? And do you think that provides any read-through to how enrollment might go once you have a broader age range introduced for your clinical trials? 87 subjects at this stage, it seems like a pretty decent number for rare diseases.

所以2也是。所以首先只是跟進 CMV。當您啟動並運行第二階段站點並為您的第三階段計劃時，考慮到您正在引入的新模式，我們是否應該考慮任何其他流程或挑戰？或者從患者應計的角度來看，這是你認為你可以很快完成的事情嗎？然後我的第二個問題是關於你對 MMA 和 PA 的自然歷史研究。您那裡的自然歷史年齡段是多少？你認為一旦你為你的臨床試驗引入了更廣泛的年齡範圍，這是否會提供任何關於註冊可能如何進行的通讀？現階段有 87 名受試者，這對於罕見病來說似乎是一個相當不錯的數字。

Thank you, Cory. It's Tal. Let me take those 2 in sequence. I don't foresee any additional challenge for enrolling the CMV, other than the Phase II or the Phase III that are platform-dependent. And I'll sort of give you the 2 reasons for that. The first is the totality of safety and tolerability data that we've seen across the portfolio are consistent with what one would expect. We haven't seen anything surprising. There's no scientific reason to expect anything untoward, and we haven't seen anything untoward in preclinical. So I think this is going to be a vaccine platform that will behave as such. In fact, the CMV data suggests that the more potent the vaccine is, the more adverse event you get, there were flu-like symptoms. But the adverse event, the type of adverse events, as I've noted, is what you'd expect. I think the other reference point is the fact that this is -- the platform as a platform is no longer considered as an adjuvanted vaccine by the agency. And I think that is also reassuring in that respect. So I don't see any hurdles that are a function of the platform to enrolling CMV or getting in the market, frankly.

謝謝你，科里。是塔爾。讓我按順序處理這兩個。除了依賴於平台的第二階段或第三階段之外，我預計註冊 CMV 不會有任何額外的挑戰。我會給你兩個原因。首先是我們在整個產品組合中看到的總體安全性和耐受性數據與人們的預期一致。我們沒有看到任何令人驚訝的事情。沒有任何科學理由可以預期會出現任何不良情況，而且我們在臨床前還沒有看到任何不良情況。所以我認為這將是一個疫苗平台，其行為將如此。事實上，CMV 數據表明，疫苗越有效，出現的不良事件就越多，出現了類似流感的症狀。但是不利事件，不利事件的類型，正如我所指出的，是你所期望的。我認為另一個參考點是這樣一個事實——作為平台的平台不再被該機構視為佐劑疫苗。我認為這在這方面也令人放心。因此，坦率地說，我沒有看到平台在註冊 CMV 或進入市場方面的任何障礙。

Your question about the natural history study is a good one. You're right. I was pleased by the rate of enrollment and the numbers that we've gotten there to-date. The age distribution is pediatric. We are seeing, I think, a median age of around 5 to 8 roughly speaking looking at the totality of the data so far. It is providing us, I think, good information as it relates to the variability, the biomarkers, the clinical endpoints, all the things we've expected to see. And I think it is substantiating our sense that the older the children are, at least those that are found at any given time points in terms of prevalence, certainly in the U.S., tend to have either undergone transplant or have deteriorating kidney function. So it all -- it is very coherent, I would say, overall, with what we're seeing in starting up sites now in trying to enroll the first subjects into the MMA trial.

你關於自然歷史研究的問題很好。你說得對。到目前為止，我對入學率和人數感到滿意。年齡分佈是小兒科。我認為，粗略地說，從目前的全部數據來看，我們看到的中位年齡大約為 5 到 8 歲。我認為，它為我們提供了與變異性、生物標誌物、臨床終點以及我們期望看到的所有事物相關的良好信息。而且我認為這證實了我們的看法，即兒童年齡越大，至少在任何給定時間點發現的患病率，當然在美國，往往要么接受了移植手術，要么腎功能惡化。所以這一切——我想說，總的來說，這與我們現在在啟動站點中看到的試圖將第一批受試者納入 MMA 試驗的情況非常一致。

And our next question comes from the line of Alec Stranahan with Bank of America.

我們的下一個問題來自美國銀行的 Alec Stranahan。

So on the ongoing follow-up from the Phase I trial of the personalized cancer vaccine. I appreciate that the objective of the Phase I is primarily to assess safety and immunogenicity. But do you intend to present any outcomes-type data from the study beyond immunogenicity, say, with this next 6 months? Or will we need to wait on the Phase II study for this sort of analysis? And then on the KRAs vaccine, is this something that Merck will report since they are the ones leading the study?

因此，關於個性化癌症疫苗的 I 期試驗正在進行的後續行動。我理解第一階段的目標主要是評估安全性和免疫原性。但是，您是否打算在接下來的 6 個月內提供除免疫原性之外的任何研究結果類型的數據？或者我們是否需要等待 II 期研究才能進行此類分析？然後關於 KRAs 疫苗，這是默克公司將報告的內容，因為他們是領導這項研究的人嗎？

Alec, it's Tal. So yes, yes to both questions. The Phase I PCV data, we will share that data once we've got a sort of a cogent totality of it. Every Phase I or every clinical trial that we do as a matter of policy and ethics in the company, we will publish, and this is no different. So at the next opportune moment when we have a body of evidence there, we will share it, including the totality of the clinical data. And in fact, I think it is the clinical data that is important to me and I think the rest of the world to assess activity here. In that regard, recall that one of the cohorts there is testing patients with previously refractory to PD-1 inhibitor, and so I think that will be meaningful data once we have it.

亞歷克，是塔爾。所以是的，對這兩個問題都是肯定的。第一階段 PCV 數據，一旦我們獲得了令人信服的整體數據，我們將共享該數據。作為公司的政策和道德問題，我們所做的每個 I 期或每個臨床試驗，我們都會發布，這也不例外。因此，在下一個適當的時候，當我們有大量證據時，我們將分享它，包括全部臨床數據。事實上，我認為臨床數據對我來說很重要，我認為世界其他地方也應該評估這裡的活動。在這方面，回想一下那裡的一個隊列正在測試以前對 PD-1 抑製劑耐藥的患者，所以我認為一旦我們有了它，這將是有意義的數據。

KRAS, you are correct. Merck is running it. And so Merck will be, I think, the party reporting out the data, and I look forward to that as well.

KRAS，你是對的。默克公司正在運行它。因此，我認為默克公司將成為報告數據的一方，我也很期待。

Okay. Great. And I had one more question, if I may. So I noticed that the follow-on Phase Ib for the hMPV+PIV3 vaccine was posted at ct.gov last week. Now looks like you've dosed the first patient in the study. So a few questions. What kind of safety metrics are required for gating between the adult and pediatric cohort? What dose levels of the vaccine will be included in the study? How quickly do you foresee the study completing? And from your conversations with the FDA, do you have a sense of potential registrational path, following the study?

好的。偉大的。如果可以的話，我還有一個問題。所以我注意到上週在 ct.gov 上發布了 hMPV+PIV3 疫苗的後續 Ib 期。現在看起來您已經給研究中的第一位患者服用了藥物。所以有幾個問題。成人和兒童隊列之間的門控需要什麼樣的安全指標？研究中將包括多少劑量水平的疫苗？您預計研究完成的速度有多快？從您與 FDA 的談話中，您是否了解研究後的潛在註冊途徑？

Those are great questions. Let me answer them in turn. The safety metrics are your typical vaccine safety metrics, so you look for safety tolerability. And we have a safety monitoring -- an independent safety monitoring committee that reviews that, and we've actually had our recent inaugural meeting with them. And so it won't be just us making that. We've got some of the world's experts in this actually looking over our shoulders and helping make those decisions. The dose level, honestly, off the top of my mind, I don't remember. It's the honest truth. I'm happy to get back to you. If it's not on the trial, let's double check that. The path to approval, that's a great question. I think as we had -- as disclosed in the past, we had an initial interaction with the agency. We had a Type C meeting in response. And we had a line of sight to the possibility to have a pivotal trial that would test both viruses together. So roughly speaking, the path there is demonstrate safety in the seropositive toddlers and then go on to a larger phase III study that would demonstrate efficacy in seronegative toddlers, because, remember, we're trying to establish immunogenicity from before anybody has been exposed. And so I can't give you a clear time to completion. And as with CMV, before one goes into a Phase III trial, we're going to have to have more in-depth discussion with the regulatory authorities before we do that.

這些都是很好的問題。讓我依次回答。安全指標是典型的疫苗安全指標，因此您需要尋找安全耐受性。我們有一個安全監控——一個獨立的安全監控委員會來審查它，實際上我們最近與他們舉行了首次會議。所以它不會只是我們做的。我們有一些這方面的世界專家實際上在關注我們並幫助做出這些決定。老實說，我不記得劑量水平了。這是誠實的事實。我很高興回复你。如果它不在試用中，讓我們仔細檢查一下。獲得批准的途徑，這是一個很好的問題。我認為，正如我們過去所披露的那樣，我們與該機構進行了初步互動。作為回應，我們召開了 C 類會議。我們看到了進行一項將兩種病毒一起測試的關鍵試驗的可能性。所以粗略地說，這條路是在血清陽性幼兒中證明安全性，然後進行更大規模的 III 期研究，以證明對血清陰性幼兒的療效，因為，請記住，我們正試圖在任何人接觸之前建立免疫原性。所以我不能給你一個明確的完成時間。與 CMV 一樣，在進入 III 期試驗之前，我們將不得不在我們這樣做之前與監管機構進行更深入的討論。

And our next question comes from the line of Hartaj Singh with Oppenheimer.

我們的下一個問題來自 Hartaj Singh 與 Oppenheimer 的對話。

I just want to ask one question about an asset that you got the furthest along, AZD8601. I know that's in partnership with AstraZeneca, the CABG study. I mean that's when you're treating patients for almost about 1.5 years now. Just any thoughts there? And could -- with the readout of this Phase II, basically a study, could AZ move that along faster or into a pivotal clinical trial? So any thoughts there? And then I just have a couple of quick follow-ups.

我只想問一個問題，關於你得到最遠的資產，AZD8601。我知道這是與 AstraZeneca 合作進行的 CABG 研究。我的意思是，那是您治療患者近 1.5 年的時間。有什麼想法嗎？並且可以——隨著第二階段的讀出，基本上是一項研究，AZ 能否將其推進得更快或進入關鍵的臨床試驗？那麼有什麼想法嗎？然後我只有幾個快速跟進。

All right, Hartaj. It's Tal. Let me take that. Two points on that trial. It is -- I mean to give AZ credit, they've designed a very informative pharmacology trial because they're using sort of state-of-the-art, as you may recall, oxygen-labeled CAD imaging to really very finally map the heart and the areas at risk. Now the challenge for them has been that the half-life of that isotope is extremely short, and so you have to find a hospital that basically has a cyclotron next door. And so what they've done, I think in this past year, has been to go and find additional sites where they can launch that trial. So they're now open, not just in Finland as they were, but actually, in Germany and in the Netherlands and are actively looking for patients. The good thing about that trial is, at the endpoint once they enroll, the subject should be relatively quickly because it is a 6 months endpoint. And the trial overall is not very large. I think that's as much insight as I have in terms of enrollment. Could they move faster? I think there are other ways that one could think of how you would develop an intracardially injected molecule. They've got a ton more expertise in this space than I do, and they're actively thinking and working along those fronts. But frankly, I'd have to defer to them to give you more color on what that could look like. And I think you had a few follow-ups. Yes.

好吧，哈塔吉。是塔爾。讓我拿那個。該試驗有兩點。這是 - 我的意思是給予 AZ 榮譽，他們設計了一個非常有用的藥理學試驗，因為他們使用了最先進的技術，正如你可能還記得的那樣，氧標記的 CAD 成像真的非常最終映射心臟和危險區域。現在他們面臨的挑戰是同位素的半衰期非常短，所以你必須找到隔壁基本上有迴旋加速器的醫院。因此，我認為在過去的一年中，他們所做的就是去尋找可以啟動該試驗的其他站點。所以他們現在開放了，不僅像以前那樣在芬蘭開放，而且實際上在德國和荷蘭也開放，並且正在積極尋找患者。該試驗的好處是，在他們註冊後的終點，受試者應該相對較快，因為這是一個 6 個月的終點。而且整個試用的規模不是很大。我認為這與我在招生方面的洞察力一樣多。他們能走得更快嗎？我認為還有其他方法可以讓您想到如何開發心內註射分子。他們在這個領域的專業知識比我多得多，而且他們正在積極思考並沿著這些方面努力。但坦率地說，我不得不聽從他們的意見，以便為您提供更多關於它可能是什麼樣子的顏色。我想你有一些後續行動。是的。

Yes. A quick one. I'll just mention them quickly. I know you had mentioned that the seropositive patients, there's -- the data seen in those in the CMV trial, that had not been seen previously in other trials. For your Phase II and your Phase III, will your stratify by seropositives? And could those be a group that you could get approval just on their own? Just any thoughts there?

是的。一個快速的。我會很快提到它們。我知道你提到過血清陽性患者，在 CMV 試驗中看到的數據，以前在其他試驗中沒有看到過。對於您的 II 期和 III 期，您會按血清陽性分層嗎？那些可以是一個你可以單獨獲得批准的團體嗎？有什麼想法嗎？

Yes. So a couple of thoughts. I think the fact that one sees this effect on seropositives, I think, is really scientifically interesting, and I've got a deep curiosity to try and figure out where it could translate to benefit. That being said, in terms of enrolling on the Phase III and the eventual label, I'd make 2 points. One, I think the Phase III will be focused on seronegatives because that's where you can see the obvious effect of preventing infection. It's hard if not impossible to actually demonstrate a clinical benefit in the seropositive, although, of course, I remain intensely curious about that. The second point to note is that FDA in their response had told us that they understand that one is not expected to demonstrate the benefit in seropositives. But in order for this vaccine to be viable in terms of access to patients and having an impact on the population, you would need a label that would encompass both populations. So the expectation is that we would demonstrate immunogen -- I'm sorry, prevention of primary infection in the seronegatives, but we would demonstrate safety and tolerability in the entire population that is all-inclusive of seropositives, and that could lead then to a label irrespective of sero status. Does that answer your question?

是的。所以有幾個想法。我認為人們看到這種對血清反應陽性的影響這一事實在科學上非常有趣，而且我有一種強烈的好奇心，想弄清楚它可以在哪裡轉化為益處。話雖這麼說，就第三階段的註冊和最終標籤而言，我會提出 2 點。第一，我認為 III 期將側重於血清陰性，因為在那裡你可以看到預防感染的明顯效果。即使不是不可能，也很難真正證明血清反應陽性的臨床益處，當然，我對此仍然非常好奇。第二點要注意的是，FDA 在他們的回應中告訴我們，他們理解人們不會在血清陽性反應中證明其益處。但是，為了使這種疫苗在接觸患者和對人群產生影響方面可行，您需要一個涵蓋兩個人群的標籤。所以期望我們會展示免疫原——對不起，預防血清陰性的原發性感染，但我們會在整個人群中展示安全性和耐受性，這包括所有的血清陽性，然後可能會導致標籤與血清狀態無關。這是否回答你的問題？

That's great, Tal. Yes.

太好了，塔爾。是的。

And our next question comes from the line of Yasmeen Rahimi with ROTH Capital Partners.

我們的下一個問題來自 Yasmeen Rahimi 與 ROTH Capital Partners 的對話。

Questions are all around PA. Congrats on recently receiving fast track designation. So the first one is for you. Can you tell me when you're thinking about dosing strategy for MA -- I'm sorry, PA, how it will differ from your strategies in 3704? And then, when we think about sort of key PD biomarker, what key biomarker, in your view, proves established proof of concepts? And then part 3 of the question is, what do we know from the literature in regards to what level of expression of PCC one needs to achieve to provide therapeutic benefit?

問題無處不在 PA。恭喜您最近獲得快速通道稱號。所以第一個適合你。當您考慮 MA 的給藥策略時，您能告訴我嗎？對不起，PA，它與您在 3704 中的策略有何不同？然後，當我們考慮某種關鍵的 PD 生物標誌物時，您認為哪種關鍵生物標誌物證明了已建立的概念證明？然後問題的第 3 部分是，我們從文獻中了解到需要達到什麼水平的 PCC 表達才能提供治療益處？

Thank you, Yasmeen. Great questions. Let me take them one at a time. The dosing strategy is roughly similar to what we expect to see in MMA. It is based on our translation of the preclinical data. We've done long-term models in animals and have used that to sort of extrapolate. So far, the technology has extrapolated nicely from all the preclinical species in the various modalities. And so I would expect this one to be similar. So I expect the dosing strategy to be once every 2 or every 3 weeks. So I think we're going to have to define that and see the effect we have on Phase I. There is a whole slew of biomarkers here that one looks at, and I think it's premature to specify which one is going to be the one. It is true, I think what you're indirectly alluding to is that the biomarkers on PA are not maybe as clear-cut as they are in MMA. I think that remains to be proven. I think the information we hope to achieve from the natural history study in terms of biomarker levels where we're collecting it should also be informative. So I mean we'll continue to update that as we learn more. I think our understanding of the literature and of our natural history level here is evolving.

謝謝你，亞斯敏。很好的問題。讓我一次帶走它們。劑量策略與我們預期在 MMA 中看到的大致相似。它基於我們對臨床前數據的翻譯。我們已經在動物身上做了長期模型，並用它來進行推斷。到目前為止，該技術已經從各種模式的所有臨床前物種中很好地推斷出來。所以我希望這一個是相似的。所以我希望劑量策略是每 2 週或每 3 週一次。所以我認為我們將不得不對其進行定義並查看我們對第一階段的影響。這裡有一大堆生物標誌物可供人們關注，我認為現在指定哪個是那個還為時過早.的確，我認為你間接暗示的是 PA 上的生物標誌物可能不像 MMA 中那樣明確。我認為這還有待證明。我認為我們希望從自然歷史研究中收集的生物標誌物水平方面的信息也應該提供信息。所以我的意思是，隨著我們了解更多，我們將繼續更新它。我認為我們對這裡的文學和自然歷史水平的理解正在發展。

In terms of the level of expression needed, I think it's hard to quantify. What we've seen from our preclinical models suggest that it is a similar level that we need of MMA in order to have the effect in the mice, be effective as profound in the PA models as it is in the MMA models. And so we expect a similar dosing level to be required for both. It may be a little bit higher given that, in PA, we are encoding for 2 proteins, not 1, right? So on a molar basis, we would expect similarity on a mg per kg. It may be a tad higher, but it's clearly within the same ballpark.

就所需的表達水平而言，我認為很難量化。我們從臨床前模型中看到的結果表明，我們需要 MMA 達到相似水平，以便在小鼠中產生效果，在 PA 模型中與在 MMA 模型中一樣有效。因此，我們預計兩者都需要類似的劑量水平。考慮到在 PA 中，我們編碼的是 2 種蛋白質，而不是 1 種，它可能會更高一些，對嗎？因此，在摩爾基礎上，我們期望每公斤毫克相似。它可能高一點，但顯然在同一個球場內。

And then if I may have a quick follow-up in regards to the antibody against chikungunya. And we're excited to see the data from the 2 doses of 0.3 mg per kg. How far out are you going to assess safety? So what are you planning to do? And what has regulators asked you to do?

然後我可以快速跟進一下針對基孔肯雅熱的抗體。我們很高興看到 2 劑 0.3 毫克/公斤的數據。您打算在多遠的時間內評估安全性？那你打算怎麼辦？監管機構要求您做什麼？

Just to clarify the question. You are asking how far are we looking at safety?

只是為了澄清這個問題。你問我們在安全方面有多遠？

Yes. Yes. Just monitoring the safety since you're giving, for the first time, 2 doses. How far out will you actually monitor these patients, and therefore, will provide for us the safety results?

是的。是的。自從您首次注射 2 劑後，只需監測安全性。您實際監測這些患者的時間有多長，因此將為我們提供安全結果？

Several weeks, I would say. I don't think it's going to be much longer than that. The reality is you've seen the adverse event profile to-date. It really is a function of the LNP, as I understand it, more than the protein that we make. We'll be continuing to follow these patients -- I'm sorry, these subjects for weeks, but I've not seen anything that leads me to expect that there's a long-term challenge here. I think the safety profile, within a week, we'll describe what it is.

幾個星期，我會說。我不認為它會比那更長。事實上，您已經看到了迄今為止的不良事件概況。據我所知，它確實是 LNP 的一個功能，而不是我們製造的蛋白質。我們將繼續跟踪這些患者——對不起，這些受試者已經跟踪了數週，但我沒有看到任何讓我期待這裡存在長期挑戰的東西。我認為安全概況，在一周內，我們將描述它是什麼。

And our last question comes from the line of Alan Carr with Needham.

我們的最後一個問題來自 Alan Carr 與 Needham 的對話。

Can you give us an update on where the other rare disease programs stay? And might those be a little bit easier to enroll? And then also, do you have any update on AZ's program with Relaxin?

您能否向我們介紹一下其他罕見病項目的進展情況？這些註冊會不會更容易一些？還有，你有關於 AZ 的 Relaxin 計劃的最新消息嗎？

Yes. So this is Tal. Let me take them. They're in their preclinical phases. Once we file the IND and we get rolling, we'll update you accordingly. And I think we don't typically comment on where exactly in the early research space they are. I think the same holds true for Relaxin, which is partnered with AstraZeneca.

是的。這就是塔爾。讓我帶走他們。他們正處於臨床前階段。一旦我們提交了 IND 並開始滾動，我們將相應地更新您。而且我認為我們通常不會評論它們在早期研究領域的確切位置。我認為與 AstraZeneca 合作的 Relaxin 也是如此。

All right. And then you also mentioned in the press release some interest in more partnerships and that sort of thing. I was wondering if you were getting at more in terms of with academic institutions or talking about partnering programs with pharma and that sort of thing.

好的。然後你還在新聞稿中提到了對更多合作夥伴關係和類似事情的興趣。我想知道你是否在與學術機構方面有更多的接觸，或者談論與製藥公司的合作項目之類的事情。

Yes. So thank you. This is Stéphane. So I mean if you look at the company history, as you know, we have done a lot of partnership. On the last 12 months, you might have observed, we have been quiet, because we are very busy. We're preparing the IPO and then spending a lot of time on the road as a newly public company. But if you look at what the team has achieved and what we believe a platform can provide in term of new medicines for patients, we have a primal abundance, which is a wonderful point to have in this industry. And so we think that we cannot take all the drugs that are coming from Stephen's team on the platform into the clinic by ourselves. And so we will continue to have dialogue with biopharmaceutical companies. If you look at the company history, we work around the clock there of our capital since inception of the company through partnerships. And we think this is a wonderful way to tap capabilities that we don't have, to tap capital that we don't have and to just increase the opportunities of getting Moderna's mRNA medicines to patients and to a finish line. And so we anticipate to continue to have new partnership set up in the quarters to come.

是的。所以謝謝。這是史蒂芬。所以我的意思是，如果你看看公司的歷史，你就會知道，我們已經建立了很多合作夥伴關係。在過去的 12 個月裡，您可能已經觀察到，我們一直很安靜，因為我們很忙。我們正在準備首次公開募股，然後作為一家新上市公司在路上花費了大量時間。但是，如果你看看團隊取得的成就以及我們相信一個平台可以為患者提供新藥的東西，我們擁有豐富的資源，這是這個行業的一大亮點。因此，我們認為我們不能自己將平台上斯蒂芬團隊提供的所有藥物帶入診所。因此，我們將繼續與生物製藥公司進行對話。如果你看一下公司的歷史，我們會發現自公司成立以來，我們通過合作夥伴關係在我們的資本中晝夜不停地工作。我們認為這是一種很好的方式來利用我們沒有的能力，利用我們沒有的資本，並增加將 Moderna 的 mRNA 藥物提供給患者並達到終點的機會。因此，我們預計將在未來幾個季度繼續建立新的合作夥伴關係。

And what's the profile of programs that you might partner versus keep in-house when you're looking at this?

當你看到這個時，你可能合作與內部保留的程序的概況是什麼？

So I mean speaking to what we have done before is looking at where do we have expertise and keep looking at biology risk. So this is what we're selling for.

所以我的意思是說我們之前所做的是研究我們在哪裡擁有專業知識並繼續關註生物學風險。所以這就是我們要賣的東西。

And this concludes today's question-and-answer session. I would now like to turn the call back to Stéphane Bancel for any further remarks.

今天的問答環節到此結束。我現在想將電話轉回給 Stéphane Bancel，以徵求任何進一步的意見。

Yes. Thank you very much for joining us today and for your questions. We look forward to seeing many of you in the coming weeks and at the JPM conference in January. We also wanted to share with you that we are planning to start an Annual Day, focused on manufacturing and digital. This new Investor Day will complement our Science Day, which usually happens in the spring, and the R&D Day, usually in September. So 2020 manufacturing and digital events will be held at our Norwood plant on the afternoon of March 4, on the back end of a Cowen conference in Boston. Juan Andres, who leads our technical development, manufacturing and quality; as well as Marcello Damiani, our Chief Digital Officer, will host the event. They will share with you what the progress their team have made in 2019 and the new initiatives they will do in 2020. We hope to see many of you on the afternoon March 4 in Norwood. Have a nice day.

是的。非常感謝您今天加入我們並提出問題。我們期待在接下來的幾周和 1 月份的 JPM 會議上見到你們中的許多人。我們還想與您分享，我們計劃啟動一個專注於製造和數字化的年度日。這個新的投資者日將補充我們通常在春季舉行的科學日和通常在九月舉行的研發日。因此，2020 年製造和數字活動將於 3 月 4 日下午在波士頓考恩會議的後端在我們的諾伍德工廠舉行。領導我們的技術開發、製造和質量的 Juan Andres；以及我們的首席數字官 Marcello Damiani 將主持此次活動。他們將與您分享他們的團隊在 2019 年取得的進展以及他們將在 2020 年採取的新舉措。我們希望在 3 月 4 日下午在諾伍德見到你們中的許多人。祝你今天過得愉快。

Ladies and gentlemen, this concludes today's conference call. Thank you for participating. You may now disconnect.

女士們，先生們，今天的電話會議到此結束。感謝您的參與。您現在可以斷開連接。