莫德納 (MRNA) 2019 Q1 法說會逐字稿

Good morning, and welcome to the Moderna First Quarter 2019 Conference Call.

早上好，歡迎參加 Moderna 2019 年第一季度電話會議。

(Operator Instructions) Please be advised that the call is being recorded.

（操作員說明）請注意，通話正在錄音。

At this time, I would like to turn the call over to Lavina Talukdar, Head, Investor Relations at Moderna.

現在，我想將電話轉給 Moderna 投資者關係主管 Lavina Talukdar。

Please proceed.

請繼續。

Thank you, operator.

謝謝你，接線員。

Good morning, and welcome to Moderna's First Quarter 2019 Conference Call to discuss financial results and business update.

早上好，歡迎參加 Moderna 2019 年第一季度電話會議，討論財務業績和業務更新。

You can access the press release issued this morning as well as the slides that we will be reviewing by going to the Investors section of our website at www.modernatx.com.

您可以訪問我們網站 www.modernatx.com 的投資者部分，查看今天上午發布的新聞稿以及我們將審閱的幻燈片。

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

今天，我們的首席執行官 Stéphane Bancel 出席了這次電話會議；斯蒂芬·霍格，我們的總裁； Tal Zaks，我們的首席醫療官；以及我們的首席財務官洛倫斯·金 (Lorence Kim)。

Before we begin, I would like to remind everyone that this conference call will include forward-looking statements.

在開始之前，我想提醒大家，本次電話會議將包含前瞻性陳述。

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.

請參閱隨附演示文稿的幻燈片 2 以及我們向 SEC 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聲明中明示或暗示的結果存在重大差異的重要風險因素。

We undertake no obligation to update or revise the information provided on this call as a result of new information or future results or developments.

我們不承擔因新信息或未來結果或發展而更新或修改本次電話會議中提供的信息的義務。

I will now pass the call over to Stéphane.

我現在將把電話轉給 Stéphane。

Thank you, Lavina.

謝謝你，拉維娜。

Good morning or good afternoon.

早上好或者下午好。

As you know, we believe that mRNA has the potential to become a new class of medicines.

如您所知，我們相信 mRNA 有潛力成為一類新的藥物。

And since Moderna's inception, we have worked hard to be the company that could become the leader in this field.

自Moderna成立以來，我們一直努力成為能夠成為該領域領導者的公司。

We believe our mRNA medicines have a potential to address large unmet medical needs and to treat diseases that are not addressable by recombinant proteins or small molecules.

我們相信我們的 mRNA 藥物有潛力解決大量未滿足的醫療需求，並治療重組蛋白或小分子無法解決的疾病。

Due to the platform nature of mRNA, we believe our mRNA medicines provide a higher probability of technical success and faster timelines to clinical trials and to the market relative to traditional medicines.

由於 mRNA 的平台性質，我們相信相對於傳統藥物，我們的 mRNA 藥物能夠提供更高的技術成功概率以及更快的臨床試驗和市場時間表。

We also believe that the manufacturing capital intensity of mRNA is materially lower than recombinant proteins.

我們還認為 mRNA 的製造資本強度大大低於重組蛋白。

We have, of course, the manufacturing at commercial scale.

當然，我們有商業規模的製造。

We will be similar to small molecule injectable in order to achieve and deliver on our goals, we continue to focus on managing the risk, especially technology risk and biology risk.

我們將類似於小分子注射劑，為了實現和交付我們的目標，我們繼續專注於管理風險，特別是技術風險和生物風險。

We believe that programs will be in the same modality of similar technology risk, meaning that once we derisk a sentinel program, they are important [breakthroughs].

我們相信，這些項目將處於類似技術風險的相同模式中，這意味著一旦我們消除哨兵項目的風險，它們就會很重要[突破]。

We believe our chikungunya antibody program will be an important clinical readout, as it uses the same formulation technology as our MMA program, our most advanced rare disease candidate.

我們相信我們的基孔肯雅抗體項目將成為重要的臨床讀數，因為它使用與我們最先進的罕見疾病候選藥物 MMA 項目相同的配方技術。

As articulated before, our corporate focus is on 3 priorities: one, to execute on the development pipeline; two, to move new development candidates in existing modalities from the lab into the clinic; and three, to continue to invest new development candidates in new modalities.

如前所述，我們公司的重點是三個優先事項：一是執行開發流程；第二，將現有模式下的新開發候選藥物從實驗室轉移到臨床；第三，繼續在新模式中投資新的發展候選者。

I will review our progress against our priority 1 on the next slide in a minute.

稍後我將在下一張幻燈片上對照優先事項 1 回顧我們的進展。

On priority 2, we are happy to announce today a new development candidate with the potential to address the rare genetic disease, glycogen storage disease type 1a or GSD1a in a systemic intracellular modality.

關於優先事項 2，我們今天很高興地宣布一種新的開發候選藥物，有可能以全身細胞內方式解決罕見遺傳病、糖原貯積病 1a 型或 GSD1a。

Stephen will provide you with an overview of the disease and our preclinical data.

斯蒂芬將為您提供該疾病的概述和我們的臨床前數據。

And priority 3, Stephen will give you a brief summary from yesterday annual Science Day presentations where we presented ongoing insights into our mRNA and delivery science that included the potential delivery of our mRNA to white blood cells.

優先事項 3，Stephen 將為您提供昨天年度科學日演講的簡要總結，其中我們介紹了對 mRNA 和遞送科學的持續見解，其中包括將 mRNA 遞送至白細胞的可能性。

While we have additional research to perform in this area, we look forward to being able to bring candidates into development as we continue working to help patients with a wide range of serious diseases.

雖然我們在這一領域還有更多的研究要做，但我們期待著能夠在我們繼續努力幫助患有各種嚴重疾病的患者的同時，將候選藥物投入開發。

Tal will give you an update about the modality in a minute, but I would like to focus on 3 programs: RSV, VZV and GSD1a.

Tal 很快就會向您介紹該模式的最新情況，但我想重點介紹 3 個項目：RSV、VZV 和 GSD1a。

RSV first.

先RSV。

As you know, our strategy across the portfolio is to create best medicine, the best medicine we can, taking advantage of mRNA flexibility and the speed with which we can advance new development candidates.

如您所知，我們整個產品組合的戰略是創造最好的藥物，利用 mRNA 的靈活性和我們推進新開發候選藥物的速度，創造最好的藥物。

We've also report Merck has been advancing an improved version of its RSV vaccine with enhanced preclinical potency and a proprietary formulation developed by Merck.

我們還報告說，默克一直在推進其 RSV 疫苗的改進版本，該疫苗具有增強的臨床前效力和默克開發的專有配方。

For this new candidate, mRNA-1172, Merck has filed an IND.

對於這一新候選藥物 mRNA-1172，默克已提交 IND 申請。

We'll note that mRNA-1172 is now reflected in our pipeline, along with MRN-1777 which is now paused in its development.

我們會注意到，mRNA-1172 現在已反映在我們的管道中，而 MRN-1777 現已暫停開發。

Merck and Moderna believe that mRNA-1172 is an improved development candidate and gives the company the highest chance of bringing a new potent RSV vaccine to people in need.

默克和 Moderna 相信 mRNA-1172 是一種改進的開發候選藥物，使該公司最有可能為有需要的人帶來一種新的強效 RSV 疫苗。

Tal will share more preclinical data in a moment, but we're looking forward to the start of the Phase 1 study.

塔爾稍後將分享更多臨床前數據，但我們期待第一階段研究的開始。

We'll then look at the clinical data from both studies of 1177 -- sorry, 1172 and 1777 and decide which development candidates to move into Phase II.

然後我們將查看 1177（抱歉，是 1172 和 1777）兩項研究的臨床數據，並決定哪些候選藥物進入第二階段。

Now let me come to VZV.

現在讓我來談談VZV。

Based on the assessments of the commercial opportunity, research priorities and other factors, Merck has discontinued preclinical development for mRNA-1278, the investigational medicine for VZV, the virus that causes shingles.

根據對商業機會、研究重點和其他因素的評估，默克公司已停止 mRNA-1278 的臨床前開發，mRNA-1278 是治療帶狀皰疹病毒（引起帶狀皰疹的病毒）的研究藥物。

Merck has returned the rights back to Moderna and the company will not continue development at this time.

默克已將權利歸還給 Moderna，該公司目前將不再繼續開發。

Let me now close by a brief note around GSD1a.

現在讓我以有關 GSD1a 的簡短說明作為結束語。

We are very pleased to work with another development candidate that is moving into GSP tox in our systemic intracellular therapeutic modality and our team, as you can imagine, are working hard to get these medicines to patients as soon as we can.

我們非常高興與另一位正在進入我們的全身細胞內治療方式中的 GSP tox 開發候選者合作，正如您可以想像的那樣，我們的團隊正在努力盡快將這些藥物提供給患者。

With this, let me now turn to Tal to give you more granularity on our pipeline.

現在，讓我請塔爾為您提供有關我們管道的更多詳細信息。

Thank you, Stéphane.

謝謝你，斯特凡。

Let me begin with reviewing our progress by modality and I'm going to start with the prophylactic vaccines.

讓我首先按方式回顧我們的進展，我將從預防性疫苗開始。

We're capping in our mRNA vaccine for respiratory syncytial virus or RSV, one of the most common causes of respiratory disease in both the very young and the elderly.

我們正在對呼吸道合胞病毒（RSV）的 mRNA 疫苗進行封頂，RSV 是幼兒和老年人呼吸道疾病的最常見原因之一。

In collaboration with Merck, we designed our vaccine to encode a membrane-anchored version of stabilized pre-fusion F protein, which elicits a neutralizing antibody response.

我們與默克公司合作，設計了疫苗來編碼穩定的融合前 F 蛋白的膜錨定版本，該蛋白可引發中和抗體反應。

In the inset, we show the intended design of the mRNA formulated in an LNP.

在插圖中，我們展示了 LNP 中配製的 mRNA 的預期設計。

We worked with Merck to identify and advance improvements to the RSV vaccine, which has led us to the identification of mRNA-1172.

我們與默克公司合作，鑑定並推進 RSV 疫苗的改進，這使我們鑑定出了 mRNA-1172。

This second vaccine has an improved RSV antigen resulting in an enhanced potency in preclinical models as well as a proprietary formulation developed by Merck.

第二種疫苗具有改進的 RSV 抗原，可增強臨床前模型的效力，並且採用默克開發的專有配方。

On the right, we have outlined data from a preclinical study in African green monkeys comparing serum neutralization titers of mRNA-1172 to mRNA-1777.

在右側，我們概述了非洲綠猴臨床前研究的數據，該研究比較了 mRNA-1172 與 mRNA-1777 的血清中和滴度。

In this study, mRNA-1172 was shown to be significantly more potent than mRNA-1777.

在這項研究中，mRNA-1172 被證明比 mRNA-1777 更有效。

As Stéphane mentioned, the IND for this new vaccine was filed earlier this month and mRNA-1777 will not move forward into the planned Phase IIa study at this time.

正如 Stéphane 提到的，這種新疫苗的 IND 已於本月早些時候提交，mRNA-1777 目前不會進入計劃的 IIa 期研究。

Let me now turn to the rest of the prophylactic vaccines.

現在讓我談談其餘的預防性疫苗。

Overall to date, approximately 1,000 healthy volunteers have been enrolled across 7 Phase I trials at doses of up to 400 micrograms.

迄今為止，大約 1,000 名健康志願者已參加了 7 項 I 期試驗，劑量高達 400 微克。

The emerging safety and tolerability profile remains consistent with that of marketed adjuvant vaccines.

新出現的安全性和耐受性特徵與市售佐劑疫苗的安全性和耐受性特徵保持一致。

We've shown promising data from 5 Phase I programs within the prophylactic vaccines modality and we continue to make progress.

我們已經展示了預防性疫苗模式內 5 個第一階段項目的有希望的數據，並且我們將繼續取得進展。

For CMV, the first 3 dose levels are now fully enrolled, and healthy volunteers have started to being dosed at 300 micrograms for the fourth dose level in that study.

對於 CMV，前 3 個劑量水平現已全部入組，健康志願者已開始在該研究中接受 300 微克的第四個劑量水平的劑量。

And VZV, based on an assessment of the commercial opportunity, research priorities and other factors, as Stéphane has discussed, Merck has discontinued preclinical development of mRNA-1278.

正如 Stéphane 所討論的，VZV 基於對商業機會、研究重點和其他因素的評估，默克已停止 mRNA-1278 的臨床前開發。

Merck has returned the rights back to us and we will not continue development at this time.

默克已將權利歸還給我們，我們目前不會繼續開發。

Turning to our cancer vaccines.

轉向我們的癌症疫苗。

We announced that we will present Phase I updates for personalized cancer vaccine at the upcoming American Society of Clinical Oncology meeting or ASCO.

我們宣布，我們將在即將召開的美國臨床腫瘤學會會議 (ASCO) 上展示個性化癌症疫苗的 I 期更新。

As a reminder, our personalized cancer vaccines are being studied as a single agent in patients with resected tumors and in combination with pembrolizumab in patients with unresectable solid tumors.

提醒一下，我們的個性化癌症疫苗正在作為單藥用於已切除腫瘤的患者中進行研究，並與派姆單抗聯合用於不可切除的實體瘤患者中進行研究。

The National Cancer Institute will also present data from its Phase I study of PCV, NCI-4650, a monotherapy for patients with advanced metastatic cancers.

美國國家癌症研究所還將展示其 PCV NCI-4650 一期研究的數據，該研究是一種針對晚期轉移性癌症患者的單一療法。

The abstract titles and presentation times can be found in the press release that went out this morning.

摘要標題和演示時間可以在今天早上發布的新聞稿中找到。

In addition, we're continuing enrollment for our PCV trial and preparing for the randomized Phase II, while the team at Merck is gearing up to enroll patients on the KRAS Phase I trial.

此外，我們正在繼續招募 PCV 試驗並為隨機 II 期試驗做準備，而默克團隊正在準備招募患者參加 KRAS I 期試驗。

For intratumoral immuno-oncology, we continue to enroll our OX40 ligand and triplet trials and prepare for the OX40 ligand Phase II cohort in ovarian cancer.

對於腫瘤內免疫腫瘤學，我們繼續招募 OX40 配體和三聯體試驗，並為卵巢癌中的 OX40 配體 II 期隊列做準備。

Also, at AACR, our partner AstraZeneca shared preclinical data that supported advancing MEDI1191 or the IL12 program into a Phase I trial.

此外，在 AACR 上，我們的合作夥伴阿斯利康分享了支持將 MEDI1191 或 IL12 項目推進 I 期試驗的臨床前數據。

AstraZeneca will lead an open-label multicenter study of intratumoral injections of IL12 alone or in combination with a checkpoint inhibitor.

阿斯利康將領導一項單獨或與檢查點抑製劑聯合瘤內註射 IL12 的開放標籤多中心研究。

Finally, the local regenerative therapeutic modalities, which includes AZD8601, our mRNA encoding for VEGF-A, AstraZeneca recently obtained clinical trial authorization to open a clinical site in the Netherlands.

最後，局部再生治療方式，包括 AZD8601（我們的 VEGF-A 編碼 mRNA），阿斯利康最近獲得了在荷蘭開設臨床中心的臨床試驗授權。

As a reminder, the Phase I study showed that AZD8601 was well tolerated and led to the translation of functional VEGF-A protein, which caused a dose-dependent increase in blood flow where it was injected.

提醒一下，I 期研究表明 AZD8601 具有良好的耐受性，並導致功能性 VEGF-A 蛋白的翻譯，從而導致注射處的血流量呈劑量依賴性增加。

Moving next to our systemic secreted therapeutics.

接下來是我們的全身分泌療法。

Let me provide some context on our first program in this modality mRNA-1944, including for chikungunya antibody.

讓我提供一些關於我們在這種模式 mRNA-1944 中的第一個程序的背景信息，包括基孔肯雅抗體。

As we were assessing the biology risk for our systemic secreted therapeutics, we began the development efforts by encoding a monoclonal antibody with the goal of inducing transient passive immunity in the recipient.

當我們評估系統分泌療法的生物學風險時，我們開始通過編碼單克隆抗體進行開發工作，目的是在接受者中誘導短暫的被動免疫。

An antibody would represent a complex protein as it requires the co-translation of 2 separate mRNAs in the correct intracellular folding and eventual secretion into the bloodstream.

抗體代表一種複雜的蛋白質，因為它需要 2 個獨立的 mRNA 在正確的細胞內折疊中共同翻譯並最終分泌到血流中。

From a safety perspective, you would expect an antiviral monoclonal antibody to be fixed, and pharmacologically, we should be able to easily measure its blood levels.

從安全角度來看，您會期望抗病毒單克隆抗體被固定，並且從藥理學角度來看，我們應該能夠輕鬆測量其血液水平。

This would then allow us to quantify the PK/PD relationship.

這將使我們能夠量化 PK/PD 關係。

In other words, how much mRNA is required to produce how much protein in a relatively straightforward manner.

換句話說，需要多少mRNA才能以相對簡單的方式產生多少蛋白質。

The lipid nanoparticle delivery system used for chikungunya antibody or mRNA-1944 is shared with our sentinel rare disease program, methylmalonic acidemia.

用於基孔肯雅病毒或 mRNA-1944 的脂質納米顆粒遞送系統與我們的前哨罕見病項目甲基丙二酸血症共享。

The Phase I design for this study is shown on Slide 18.

本研究的第一階段設計如幻燈片 18 所示。

We're conducting it in healthy volunteers, so it should give us a read on the safety and tolerability of this formulation.

我們是在健康志願者中進行的，因此它應該讓我們了解該製劑的安全性和耐受性。

The pharmacological goal that I mentioned is to determine how much antibody we can produce as a result of systemically administered mRNA and whether we may be able to offer people passive immunity against infection by this virus, which today has neither a vaccine nor specific therapies available.

我提到的藥理學目標是確定通過全身施用 mRNA 可以產生多少抗體，以及我們是否能夠為人們提供針對這種病毒感染的被動免疫力，目前這種病毒既沒有疫苗也沒有特定的療法。

We recently completed enrollment of all 8 subjects in the second dose cohort in healthy volunteers treated at 0.3 milligram per kilogram in this Phase I study and I look forward to sharing more once we have a complete picture of the data.

我們最近在這項I 期研究中完成了健康志願者第二劑量隊列中所有8 名受試者的入組，接受劑量為0.3 毫克/公斤，一旦我們掌握了完整的數據，我期待著分享更多信息。

Also, our chikungunya antibody preclinical data was just accepted for publication in the Journal of Science Immunology.

此外，我們的基孔肯雅抗體臨床前數據剛剛被《科學免疫學雜誌》接受發表。

We're continuing to move our Fabry and Relaxin programs towards clinical trials and look forward to providing you with an update at a later date.

我們正在繼續將 Fabry 和 Relaxin 項目推向臨床試驗，並期待稍後為您提供最新信息。

Finally, let me turn to our systemic intracellular therapeutics.

最後，讓我談談我們的系統性細胞內療法。

From methylmalonic acidemia or MMA, we're currently in the process of initiating sites for the Phase I trial.

對於甲基丙二酸血症或 MMA，我們目前正在啟動 I 期試驗的地點。

We have 45 patients enrolled in our MaP natural history study for methylmalonic acidemia and propionic acidemia.

我們有 45 名患者參加了甲基丙二酸血症和丙酸血症的 MaP 自然史研究。

26 of these are MMA patients and 19 are PA patients.

其中 26 名是 MMA 患者，19 名是 PA 患者。

In addition, the European Commission has adopted the recommendation from the Committee of Orphan Medicinal Products for orphan designation for mRNA-3927, our PA development candidate, further supporting its advancement.

此外，歐盟委員會還採納了孤兒藥產品委員會的建議，將 mRNA-3927（我們的 PA 開發候選藥物）指定為孤兒藥，進一步支持其進展。

We continue to progress mRNA-3927 for propionic acidemia and mRNA-3283 for phenylketonuria with the goal of bringing them to the clinic.

我們繼續開髮用於丙酸血症的 mRNA-3927 和用於苯丙酮尿症的 mRNA-3283，目標是將它們推向臨床。

I'm really excited about the opportunity for the new development candidate within our systemic intracellular therapeutic modalities and will now turn it over to Stephen who will introduce this candidate for glycogen storage disease type 1a or GSD1a.

我對我們的全身細胞內治療方式中新的候選藥物開發機會感到非常興奮，現在將其交給 Stephen，他將介紹該候選藥物用於治療 1a 型或 GSD1a 糖原貯積病。

Thanks, Tal.

謝謝，塔爾。

So glycogen storage disease type 1a or GSD1a is a rare inherited metabolic disorder resulting from a deficiency in an enzyme called glucose 6-phosphatase, or G6Pase for short.

因此，1a 型糖原貯積病或 GSD1a 是一種罕見的遺傳性代謝性疾病，由葡萄糖 6-磷酸酶（簡稱 G6Pase）缺乏引起。

The G6Pase enzymes involved in the metabolic pathways to allow the liver and, to a lesser extent, the kidney to maintain the level of glucose in the blood during fasting.

G6P 酶參與代謝途徑，使肝臟和腎臟在較小程度上維持禁食期間血液中的葡萄糖水平。

After a couple of hours in a normal healthy person, most of the glucose from your last meal have been consumed by tissues.

對於正常健康的人來說，幾個小時後，上一頓飯中的大部分葡萄糖已被組織消耗掉。

So as glucose levels start to fall, most of the tissues in our bodies will convert to using -- should convert from using glucose for energy to other sources such as lipids or triglycerides.

因此，當葡萄糖水平開始下降時，我們體內的大多數組織將轉化為利用葡萄糖作為能量，而轉化為其他來源，例如脂質或甘油三酯。

But cells in our brains are unable to make that switch and are dependent upon glucose to survive.

但我們大腦中的細胞無法進行這種轉換，並且依賴葡萄糖才能生存。

So our livers take over the responsibility for making and releasing glucose into the bloodstream to keep the brain alive.

因此，我們的肝臟承擔了製造葡萄糖並將其釋放到血液中以保持大腦活力的責任。

This process involves 2 different metabolic processes: first, glycogenolysis or the breakdown of liver-stored glucose for release; and gluconeogenesis or the conversion of other substrates into glucose.

這個過程涉及2個不同的代謝過程：首先，糖原分解或分解肝臟儲存的葡萄糖以釋放；和糖異生或其他底物轉化為葡萄糖。

Glucose 6-phosphatase catalyzes the last step in both of those processes in the ER and liver.

葡萄糖 6-磷酸酶催化 ER 和肝臟中這兩個過程的最後一步。

Now the good news for most of us is that process happens automatically, every day and particularly as we fast overnight, our liver takes over the responsibility for keeping our brain alive.

現在，對我們大多數人來說，好消息是這個過程每天都會自動發生，特別是當我們禁食過夜時，我們的肝臟接管了保持大腦活力的責任。

But people suffering from GSD1a are unable to maintain that blood glucose during a fast.

但患有 GSD1a 的人無法在禁食期間維持血糖水平。

As a result, they suffer from threatening hypoglycemia or low blood glucose that can also result in debilitating neurologic effects, even death.

結果，他們遭受威脅性低血糖或低血糖，這也可能導致神經系統衰弱，甚至死亡。

Over time, the lack of the enzyme can also lead to a wide range of severe metabolic derangements such as hyperlipidemia from the buildup of lipids, lactic acidemia and enlargement disease in livers.

隨著時間的推移，缺乏這種酶還會導致一系列嚴重的代謝紊亂，例如脂質堆積引起的高脂血症、乳酸血症和肝臟腫大疾病。

In order to prevent life-threatening hypoglycemia, these patients must consume sugar regularly, almost continuously via complex sugars such as corn starch.

為了防止危及生命的低血糖，這些患者必須定期攝入糖，幾乎連續不斷地通過玉米澱粉等複合糖攝入糖。

Patients need to wake several times a night, every night to consume this corn starch.

患者需要每晚醒來數次，每天晚上才能消耗這種玉米澱粉。

And some younger patients even need to have gastric tubes placed to facilitate this feeding or be placed on continuous IV glucose strips.

一些年輕患者甚至需要放置胃管以方便餵養或放置連續靜脈注射葡萄糖條。

Clearly, there needs to be an improvement in the standard of care.

顯然，護理標準需要提高。

Now GSD1a occurs in about 1 in 100,000 live births, with a slightly higher prevalence among Ashkenazi Jews.

現在，GSD1a 的發生率約為十萬分之一，在德系猶太人中患病率略高。

That means that approximately 6,500 patients across the U.S. and EU exist.

這意味著美國和歐盟約有 6,500 名患者。

We believe our platform can address GSD1a by replacing that missing information in those liver cells and helping those patients control their glucose.

我們相信我們的平台可以通過替換那些肝細胞中缺失的信息並幫助這些患者控制血糖來解決 GSD1a 問題。

Now just to review a little bit of the preclinical data.

現在只是回顧一下臨床前數據。

We demonstrated proof of concept for G6Pase m-RNA therapies in multiple in-vivo studies.

我們在多項體內研究中展示了 G6Pase mRNA 療法的概念驗證。

First, looking at the upper left-hand panel, we've been able to demonstrate dose-dependent in-vivo pharmacology in the animal knockout model; in this case, mice.

首先，看左上圖，我們已經能夠在動物基因敲除模型中證明劑量依賴性體內藥理學；在這種情況下，是老鼠。

As you can see, at escalating doses from 0.2 milligrams per kilogram up to 1 milligram per kilogram, we achieved a dose-dependent normalization of the blood glucose of these -- in these animals during fast.

正如您所看到的，當劑量從每公斤 0.2 毫克增加到每公斤 1 毫克時，我們在這些動物禁食期間實現了血糖的劑量依賴性正常化。

It's exciting to see as that translates into other markers of activity as well.

令人興奮的是，這也轉化為其他活動標記。

The panel in the middle to the right shows triglycerides and shows across all dose levels tested here a normalization of those triglyceride levels.

右側中間的面板顯示甘油三酯，並顯示此處測試的所有劑量水平的甘油三酯水平的標準化。

Lastly, in looking at the liver weights of these animals after 24 hours after a dose, we showed normalization -- partial normalization relative to control of the liver weights in these animals showing broad-based metabolic effects.

最後，在觀察給藥後 24 小時後這些動物的肝臟重量時，我們顯示出正常化——相對於這些動物的肝臟重量控制的部分正常化，顯示出廣泛的代謝效應。

On the far right-hand side, we are showing a 7-week study with repeat dosing showing the ability to normalize blood glucose levels during fast in these animals up to 5 doses.

在最右邊，我們展示了一項為期 7 週的重複給藥研究，顯示這些動物在禁食期間最多 5 次給藥能夠使血糖水平正常化。

We believe this data supports the development of GSD1 -- mRNA-3745 in these proof of concept studies.

我們相信這些數據支持這些概念驗證研究中 GSD1 - mRNA-3745 的開發。

And this data was recently presented at ASGCT and we're excited about the potential for this new development candidate to bring significant clinical benefit to GSD1a patients.

該數據最近在 ASGCT 上公佈，我們對這一新開發候選藥物為 GSD1a 患者帶來顯著臨床益處的潛力感到興奮。

So returning to the pipeline on 525, you'll now see GSD1a, our fifth rare metabolic disease, enter development.

因此，回到 525 的研發過程中，您現在將看到 GSD1a（我們的第五種罕見代謝疾病）進入開發階段。

We look forward to doing everything we can to help these patients and other patients suffering from these debilitating diseases.

我們期待盡一切努力幫助這些患者和其他患有這些使人衰弱的疾病的患者。

Changing gears, I want to talk a little bit about our Science Day efforts and briefly recap some of the discussions from yesterday.

換個話題，我想談談我們在科學日所做的努力，並簡要回顧一下昨天的一些討論。

We had the pleasure for doing our second Annual Science Day and we created Science Day to provide a window into our investments in the research platform and to create new generations of technologies that will enable our future pipeline.

我們很高興舉辦第二屆年度科學日，我們創建科學日是為了提供一個窗口，了解我們對研究平台的投資，並創造新一代技術，使我們的未來管道成為可能。

I co-hosted the Science Day with Melissa Moore, the Chief Scientific Officer of our platform.

我與我們平台的首席科學官 Melissa Moore 共同主持了科學日活動。

Now with over 200 dedicated scientists focusing on advancing technology underlying our investigation medicines, it's impossible to summarize everything.

現在，超過 200 名專注的科學家專注於推進我們研究藥物的技術進步，因此不可能概括一切。

In the last 3 years, we published 25 peer-review manuscripts in leading journals with 11 in the last year alone.

過去 3 年裡，我們在領先期刊上發表了 25 篇同行評議手稿，其中僅去年就發表了 11 篇。

So for Science Day, Melissa and I tried to select a few vignettes that illustrate the breadth and depth of the basic science we're pursuing at Moderna.

因此，在科學日，梅麗莎和我試圖選擇一些小插曲來說明我們在 Moderna 所追求的基礎科學的廣度和深度。

These fall broadly into 2 categories: our mRNA science and our delivery science.

這些大致分為兩類：我們的 mRNA 科學和我們的遞送科學。

And as you can see from the agenda here we divide the time roughly between the 2. For those who are interested in reviewing the Science Day content, I'll direct you to a link either on our website or the PR release this morning, but some of the key highlights are on the next few slides.

正如您從此處的議程中看到的，我們大致將時間分為 2 部分。對於那些有興趣回顧科學日內容的人，我將引導您訪問我們網站或今天早上 PR 發布上的鏈接，但是接下來的幾張幻燈片將介紹一些關鍵亮點。

So first in the mRNA Science Day, we demonstrated some of the ways in which we're making our vaccines and therapeutics more potent and safer.

因此，首先在 mRNA 科學日，我們展示了一些使我們的疫苗和治療方法更有效、更安全的方法。

We shared some of the latest in-vivo characterization of the nature of the innate immune response and the importance of uridine modification to making immune silent messenger RNA medicines.

我們分享了先天免疫反應性質的一些最新體內特徵以及尿苷修飾對於製造免疫沉默信使 RNA 藥物的重要性。

We showed -- we shared advances in how we're using design of our mRNA to maximize potency, including several-fold improvements in the amount of protein that were being produced in rare disease animal models.

我們展示了——我們分享瞭如何利用 mRNA 設計來最大限度地發揮效力的進展，包括將罕見疾病動物模型中產生的蛋白質數量提高數倍。

We also shared how secondary structure is being designed into our messenger RNA to create buffer space between ribosomes as they translate it to prevent, what we've been calling ribosomal traffic jams.

我們還分享瞭如何將二級結構設計到我們的信使 RNA 中，以便在核醣體翻譯時在核醣體之間創建緩衝空間，以防止我們所說的核醣體交通堵塞。

This can increase mRNA half-life and decrease the need for dosing.

這可以增加 mRNA 半衰期並減少給藥需求。

Lastly, we shared some of the exciting work we're doing in physics on nanoparticles.

最後，我們分享了我們在納米粒子物理學方面所做的一些令人興奮的工作。

Understanding the formulation, their surface characterization and how to make them more potent and effective.

了解配方、其表面特徵以及如何使其更加有效。

The second half of the Science Day focused on advances in delivery science, and specifically, introducing our immune nanoparticle research program.

科學日的後半場重點關注輸送科學的進展，特別是介紹我們的免疫納米顆粒研究計劃。

As Stéphane mentioned, this is an effort to deliver messenger RNA broadly in the immune system to a wide range of cell types including lymphocytes.

正如 Stéphane 提到的，這是一項將免疫系統中的信使 RNA 廣泛傳遞到包括淋巴細胞在內的多種細胞類型的努力。

And we shared some of the translational data we have across species demonstrating progress in that space.

我們分享了一些跨物種的轉化數據，展示了該領域的進展。

The key features of the immune nanoparticle research and program are dose-dependent pharmacology in all major cell types of the immune system, a system-wide effect.

免疫納米顆粒研究和計劃的關鍵特徵是免疫系統所有主要細胞類型中的劑量依賴性藥理學，即全系統效應。

As always across all of our efforts in delivery, dose-dependent pharmacology is critical to our success.

一如既往，在我們所有的給藥努力中，劑量依賴性藥理學對於我們的成功至關重要。

We also demonstrate how we're transiently expressing proteins that confer cells with new -- cells with new phenotypes and functions and drive responses, how we use mRNA software to select the cell type in which we express proteins and how we've been driving trafficking of immune cells to new tissues to drive desired cell-to-cell interactions.

我們還展示了我們如何瞬時表達蛋白質，賦予細胞新的表型和功能並驅動反應，我們如何使用 mRNA 軟件來選擇我們表達蛋白質的細胞類型，以及我們如何推動販運將免疫細胞轉移到新組織中，以驅動所需的細胞間相互作用。

While this work is still in the research and preclinical phase, we are obviously incredibly excited about the potential it brings to treating a wide range of diseases, including cancer, autoimmune disease and neurodegenerative disease.

雖然這項工作仍處於研究和臨床前階段，但我們顯然對其治療多種疾病（包括癌症、自身免疫性疾病和神經退行性疾病）的潛力感到非常興奮。

So with that, I'll now turn over the call to Lorence who'll walk through all the financials.

因此，我現在將把電話轉給洛倫斯，他將詳細介紹所有財務狀況。

Thank you, Stephen.

謝謝你，斯蒂芬。

In today's press release, we reported our first quarter 2019 financial results.

在今天的新聞稿中，我們報告了 2019 年第一季度的財務業績。

Please note these results are unaudited.

請注意，這些結果未經審計。

We ended Q1 2019 with cash, cash equivalents and investments of $1.55 billion, and this compares to $1.69 billion at the end of 2018.

截至 2019 年第一季度，我們的現金、現金等價物和投資為 15.5 億美元，而 2018 年底為 16.9 億美元。

Let me highlight 2 cash flow metrics, which provide a direct view on cash use.

讓我重點介紹兩個現金流量指標，它們可以直接反映現金使用情況。

These are better given the quantity of deferred revenue stock-based compensation and depreciation that's embedded in our operating income.

考慮到我們營業收入中包含的基於股票的遞延收入補償和折舊的數量，這些更好。

Net cash used in operations was approximately $144 million for the first quarter of 2019, that compares to $111 million for the first quarter of 2018.

2019 年第一季度運營使用的淨現金約為 1.44 億美元，而 2018 年第一季度為 1.11 億美元。

Please note that Q1 of 2019 and 2018 include $22 million and $25 million, respectively of in-licensing payments.

請注意，2019 年和 2018 年第一季度分別包括 2200 萬美元和 2500 萬美元的許可付款。

Secondly, cash used for purchases of the property and equipment was $8 million for Q1 2019 compared to $32 million for Q1 '18.

其次，2019 年第一季度用於購買財產和設備的現金為 800 萬美元，而 18 年第一季度為 3200 萬美元。

Revenue for Q1 2019 was $16 million as compared to $29 million for Q1 '18.

2019 年第一季度的收入為 1600 萬美元，而 18 年第一季度的收入為 2900 萬美元。

Note that on January 1, 2019, we adopted the new revenue recognition standard ASC606, using the modified retrospective transition method applied to those contracts, which were not completed as of January 1. The decrease in total revenue was mainly attributable to the decrease in collaboration revenue across all of our strategic alliances, particularly AstraZeneca and Merck, driven by the adoption of the new revenue standard.

請注意，2019年1月1日，我們採用了新的收入確認標準ASC606，對截至1月1日尚未完成的合同採用了修改後的追溯過渡法。總收入減少主要是由於合作減少我們所有戰略聯盟的收入，特別是阿斯利康和默克，都受到採用新收入標準的推動。

Total revenue under the previous revenue recognition standard would have been $38 million for Q1 2019.

根據之前的收入確認標準，2019 年第一季度的總收入將為 3800 萬美元。

R&D expenses for Q1 2019 were approximately $131 million compared to $90 million for Q1 '18, the increase was primarily due to an increase in personnel-related costs, including stock-based comp, mainly driven by an increase in number of employees supporting research and development programs, an increase in clinical trial and manufacturing costs, an increase in lab supplies and materials for preclinical studies and clinical trials, and an increase in consulting and outside services costs.

2019 年第一季度的研發費用約為1.31 億美元，而18 年第一季度的研發費用為9000 萬美元，這一增長主要是由於人員相關成本的增加，包括基於股票的補償，這主要是由於支持研究和開發的員工數量增加所致。開發計劃、臨床試驗和製造成本的增加、臨床前研究和臨床試驗的實驗室用品和材料的增加以及諮詢和外部服務成本的增加。

G&A expenses for Q1 2019 were approximately $27 million compared to $16 million in Q1 of '18.

2019 年第一季度的一般管理費用約為 2700 萬美元，而 18 年第一季度為 1600 萬美元。

That increase was mainly attributable to an increase in personnel-related costs, including stock-based compensation, primarily driven by an increase in the number of employees and consulting and outside services cost, both of which were related to operating as a publicly traded company.

這一增長主要歸因於人員相關成本的增加，包括基於股票的薪酬，這主要是由員工數量以及諮詢和外部服務成本的增加推動的，這兩者都與作為上市公司的運營有關。

So with that, I'll hand the call back over to Stéphane.

因此，我會將電話轉回給 Stéphane。

Thank you, Lorence.

謝謝你，洛倫斯。

To close our remarks, I would like to reiterate that our team is very focused on the execution of all the 3 priorities: number one, advancing development pipeline; number two, investing in new development candidates within the 6 existing modalities as we just announced this morning on GSD1a; and investing in new modalities like the immuno-nano particles presented yesterday at the Science Day to deliver and manage white blood cells.

作為我們發言的結束語，我想重申，我們的團隊非常專注於執行所有三個優先事項：第一，推進開發渠道；第二，正如我們今天早上剛剛在 GSD1a 上宣布的那樣，在 6 種現有模式中投資新的開發候選者；並投資新的模式，例如昨天在科學日上展示的免疫納米顆粒，以輸送和管理白細胞。

We're very excited about 2019 and 2020 as we anticipate having a lot of clinical readouts both in Phase I as well as Phase II start and readout.

我們對 2019 年和 2020 年感到非常興奮，因為我們預計在 I 期以及 II 期啟動和讀數中都會有大量臨床讀數。

I believe that Moderna is operating from a place of clinical strength.

我相信 Moderna 的運營具有臨床優勢。

I'm pleased with our progress.

我對我們的進展感到滿意。

In effort by our mRNA platform, our large development pipeline continues to progress based on the data we're generating from now around 1,000 healthy volunteers and patients enrolled in our trials across all medicines, preprograms in or planning for Phase II, 6 positive Phase I readouts, 5 ongoing Phase I trials, 3 open INDs awaiting Phase I trials.

在我們的mRNA 平台的努力下，我們的大型開發管道根據我們現在生成的數據繼續取得進展，大約1,000 名健康志願者和患者參加了我們所有藥物的試驗，II 期預編程或計劃，6 個陽性I 期試驗讀數，5 個正在進行的 I 期試驗，3 個開放 IND 等待 I 期試驗。

If you look at the pipeline by therapeutic area, I'm very proud of where we stand today.

如果你按治療領域來觀察管道，我對我們今天的處境感到非常自豪。

We have 5 immuno-oncology programs, OX40 ligand and PCV, which are being prepared for Phase II by our teams.

我們有 5 個免疫腫瘤學項目，OX40 配體和 PCV，我們的團隊正在為 II 期項目做準備。

The triplet, which continues the dose escalation in Phase I, and 2 open INDs for KRAS and IL12.

該三聯藥物在第一階段繼續劑量遞增，並有 2 個針對 KRAS 和 IL12 的開放 IND。

With our 5 rare disease programs: MMA, we're continuing to enroll in the natural history study and our teams are currently in progress for initiating sites for Phase I with an open IND.

通過我們的 5 個罕見疾病項目：MMA，我們將繼續參加自然歷史研究，我們的團隊目前正在為具有開放 IND 的 I 期啟動地點進行工作。

PA, which recently got granted orphan disease designation by the EC.

PA 最近被 EC 授予孤兒疾病稱號。

PKU, Fabry and now GSD1a in preclinical tox studies.

PKU、Fabry 和現在的 GSD1a 都在臨床前毒性研究中。

Free vaccines for major unmet medical needs: RSV, CMV and our combo, hMPV PIV3.

滿足主要未滿足醫療需求的免費疫苗：RSV、CMV 和我們的組合疫苗 hMPV PIV3。

We're now more than 775 employees who are very committed to change patients' life through mRNA science.

我們現在擁有超過 775 名員工，他們非常致力於通過 mRNA 科學改變患者的生活。

On Norwood facility, which we believe is a strategic asset to enable the company to scale and ensure high-quality medicine as we do our clinical trials, and a strong balance sheet.

在諾伍德工廠，我們認為這是一項戰略資產，使公司能夠在進行臨床試驗時擴大規模並確保高質量的藥品，並擁有強大的資產負債表。

We know that we have a very special opportunity and the team is very committed to delivering on the promise of our science and bringing forward a new class of medicines for patients.

我們知道我們有一個非常特殊的機會，團隊非常致力於兌現我們科學的承諾，為患者提供新型藥物。

I would like to end our remarks by thanking the many people who participate in our clinical studies, including obviously our patients, healthy volunteers and the physicians.

在結束我們的發言時，我想感謝參與我們臨床研究的許多人，當然包括我們的患者、健康志願者和醫生。

With that, we'll now be happy to take your questions.

這樣，我們現在很樂意回答您的問題。

Operator?

操作員？

(Operator Instructions) Our first question comes from 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 2 from me.

我猜我有2個。

So on RSV, can you maybe just clarify a little bit what specifically is Merck hoping to achieve with the new formulation and the neoantigen selection relative to what you've achieved so far?

那麼，關於 RSV，您能否澄清一下默克公司希望通過新配方和新抗原選擇相對於您迄今為止所取得的成就具體實現什麼目標？

And then, I guess, just remind us when you started a similar point with 1777, how long did it take you to progress to being Phase II ready?

然後，我想，請提醒我們，當您在 1777 年開始類似的點時，您花了多長時間才為第二階段做好準備？

And then I have a follow-up.

然後我有一個後續行動。

Sure, Stephen?

當然，斯蒂芬？

Sure.

當然。

Obviously, we're pretty excited about that one, the 1172 and we're really pleased that Merck's filed the IND already, and it's moving quickly.

顯然，我們對 1172 感到非常興奮，我們非常高興默克已經提交了 IND，而且進展很快。

You saw the summary of the data in primates.

您看到了靈長類動物的數據摘要。

It's been hard to argue with the substantial improvement that we demonstrated there.

很難對我們在那裡展示的實質性改進提出異議。

1777, just referencing that slide, shows superior titers to a natural RSV infection, which was there in gray.

1777，僅引用該幻燈片，顯示出優於自然 RSV 感染的滴度，其中灰色。

But 1172 was qualitatively and quantitatively several-fold higher.

但1172在質量和數量上都高出好幾倍。

And so in the face of those improvements, we felt compelled and that it makes a ton of sense to move forward.

因此，面對這些改進，我們感到有必要，並且繼續前進是很有意義的。

Now what are those improvements just quickly, I think, you hit on them, Matt, but the first is antigen design.

現在，我想，你很快就想到了這些改進，馬特，但首先是抗原設計。

This is still a pre-fusion F protein, but it's been further stabilized to improve potency and immunogenicity, so that's a desirable feature.

這仍然是融合前的 F 蛋白，但它已被進一步穩定以提高效力和免疫原性，因此這是一個理想的特徵。

And then the second scientific improvement went into the program, obviously, is the switch from a legacy lipid nanoparticle to a Merck proprietary formulation, that has some improved features.

然後，該計劃的第二個科學改進顯然是從傳統的脂質納米顆粒轉變為具有一些改進功能的默克專有配方。

Those improved features, I'll let Merck talk about at a future date, but we think they are a part of what's happening in terms of the improvement here.

這些改進的功能，我將讓默克在將來討論，但我們認為它們是這裡改進的一部分。

And ultimately, the combination of antigen and formulation leads to the qualitative improvement you see there.

最終，抗原和配方的結合會帶來您所看到的質量改進。

It does, at this point, mean a pause to 1777 moving to Phase IIa as described, but as far -- our goal is the best RSV vaccine possible, with the highest probability of success and as much as we wanted to see the 1777 data, it's clearly the right answer to look for 1172 first, given the multifold improvement that's been demonstrated in African green monkeys.

在這一點上，這確實意味著 1777 年暫停，轉向 IIa 階段，但就目前而言，我們的目標是盡可能最好的 RSV 疫苗，成功的可能性最高，並且我們希望看到 1777 年的數據，考慮到非洲綠猴的多倍改進，首先尋找1172 顯然是正確的答案。

In general, our experience has translated and you know that well.

總的來說，我們的經驗已經得到了轉化，這一點您也很清楚。

Things that we've been able to see in terms of preclinical species like primates for vaccines has translated into humans.

我們在靈長類動物等臨床前物種身上看到的疫苗已經轉化為人類。

So if this translates in Phase I relatively quickly for 1172, which we hope and expect it will, this is the vaccine that we should advance further in development to Phase II and Phase III.

因此，如果這在第一階段相對較快地轉化為 1172（我們希望並預期會如此），那麼我們應該進一步推進該疫苗的開發，進入第二階段和第三階段。

And Matthew, this is Tal.

馬修，這是塔爾。

In terms of time lines, if you look historically, it typically takes you 12 to 18 months for a Phase I vaccine trial.

就時間線而言，如果回顧歷史，I 期疫苗試驗通常需要 12 至 18 個月的時間。

It's done in healthy volunteers, so it's a fairly straightforward simple design.

它是在健康志願者身上完成的，所以這是一個相當簡單的設計。

I can't give you a forward-looking guidance here, but I would note that Merck has recently filed its IND and they will be leading the execution of this trial.

我不能在這裡給你前瞻性的指導，但我要指出的是，默克最近已經提交了 IND，他們將領導這項試驗的執行。

Obviously, the team there knows what they're doing in terms of vaccine trials.

顯然，那裡的團隊知道他們在疫苗試驗方面正在做什麼。

Okay.

好的。

Great.

偉大的。

That's helpful.

這很有幫助。

And then the second question is on chikungunya.

第二個問題是關於基孔肯雅熱的。

I know you've entered the second cohort.

我知道你已經進入第二批了。

Do you have any view on how many cohorts you need to get through before you feel like you have enough data to talk about with that modality?

在您覺得自己有足夠的數據可以用這種方式進行討論之前，您對需要經過多少個隊列有什麼看法嗎？

This is Tal.

這是塔爾。

The trial that's currently designed has 4 dose levels, that was predicted based on our expectation that translates the data from the nonhuman primate that you've seen.

目前設計的試驗有 4 個劑量水平，這是根據我們的預期預測的，翻譯了您所見過的非人類靈長類動物的數據。

I think we're on track with that design.

我認為我們正在按計劃進行該設計。

We've been enrolling fairly consistently, and as we said, we're at the second dose level.

我們的入組情況相當穩定，正如我們所說，我們處於第二劑量水平。

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

我們的下一個問題來自高盛的 Salveen Richter。

It's Ross on for Salveen.

羅斯替補薩爾文。

Just in terms of mRNA-1172 and RSV and the decision to move forward the more optimized program, is this something that we should kind of think that may occur in other programs going forward as you continue to test new formulations of your current compounds in clinical candidates?

就 mRNA-1172 和 RSV 以及推進更優化計劃的決定而言，當您繼續在臨床中測試當前化合物的新配方時，我們是否應該認為這可能會發生在未來的其他計劃中候選人？

So we continue -- with any program we advance, we're always looking at whether there are improvements.

因此，我們繼續——對於我們推進的任何計劃，我們總是關注是否有改進。

And yes, there are always -- there sometimes can be small improvements you can make.

是的，總是有的——有時你可以做出一些小的改進。

I think the question gets more complicated where you start to see 5-fold improvements kind of like we're talking here with 1172 where qualitatively that improvement is so strong and in the background of what's been happening in RSV vaccines more generally, it makes sense to bring the best vaccine forward first and quickly, particularly when you are this close after the lead, in this case 1777.

我認為問題變得更加複雜，當你開始看到5 倍的改進時，有點像我們在這裡談論1172，從質量上講，這種改進非常強大，並且在RSV 疫苗更普遍發生的情況的背景下，這是有道理的首先并快速地推出最好的疫苗，特別是當您距離領先優勢如此之近時，在本例中為 1777。

That isn't something that we can predict happening broadly across many programs or efforts.

我們無法預測許多計劃或努力會廣泛發生這種情況。

And in general, as you can see with other vaccines in our pipeline, we haven't been doing this.

總的來說，正如您在我們正在研發的其他疫苗中看到的那樣，我們還沒有這樣做。

And so just pointing at the history here, it's more of by exception a situation where this has been happening and that's probably what we would expect about the future.

因此，只要回顧一下這裡的歷史，這更多的是一種例外情況，這種情況已經發生，這可能就是我們對未來的期望。

This is Tal.

這是塔爾。

I mean just to add a couple of points.

我的意思只是補充幾點。

I think it's one of the fascinating things of beauty of our platform that we have relatively rapid improvements and that the coding-like nature of mRNA lends itself to those improvements.

我認為我們平台的迷人之處之一是我們的改進相對較快，而 mRNA 的編碼性質有助於這些改進。

So if you look at our history, for example, in the personalized cancer vaccine, we've been able to take it to the next level by increasing the number of neoantigens from 20 to 34.

因此，如果你看看我們的歷史，例如在個性化癌症疫苗方面，我們已經能夠通過將新抗原的數量從 20 種增加到 34 種，將其提升到一個新的水平。

And as the team worked through what that means both in terms of mRNA length and sequence optimization, we found a way within the clinic to actually introduce that within the current clinical paradigm.

當團隊研究 mRNA 長度和序列優化的含義時，我們在臨床中找到了一種方法，可以在當前的臨床範例中實際引入這一點。

Now of course, the PCV is a unique type of drug in that regard and I give the FDA a lot of credit for working with us to enable that.

當然，從這方面來說，PCV 是一種獨特的藥物，我非常感謝 FDA 與我們合作實現這一目標。

So where we can, we always try to optimize for the best medicine that we can and it depends on the specifics of the product as to what's the best way to do it.

因此，在可能的情況下，我們總是盡力優化最佳藥物，這取決於產品的具體情況，以了解最佳方法。

Great.

偉大的。

And then I just have one follow-up on the chikungunya antibody.

然後我只對基孔肯雅病毒抗體進行了一項後續調查。

How can we think about the clinical bar here as we approach the data readout, like what are the level -- the antibody levels that we should expect to see to confer this passive immunity in humans?

當我們接近數據讀出時，我們如何考慮這裡的臨床條形，比如我們應該期望看到的水平是多少，以賦予人類這種被動免疫力？

So as you will see in the preclinical data that as we said that's recently been accepted for publication, so it should come out soon, the target expression for this antibody is about 1 microgram per mL in terms of what we think is going to be a therapeutic concentration or a concentration that will -- should prevent from infection based on the totality of the preclinical data.

正如您將在臨床前數據中看到的那樣，正如我們所說，該數據最近已被接受發表，因此應該很快就會發布，該抗體的目標表達約為每毫升1 微克，我們認為這將是根據全部臨床前數據，治療濃度或應預防感染的濃度。

And that was easily achieved within the dose levels that we've cleared for in the toxicology studies and the preclinical studies.

在我們在毒理學研究和臨床前研究中確定的劑量水平內，這很容易實現。

So from a target product profile for this application what we're shooting for is 1 microgram per mL.

因此，從該應用的目標產品概況來看，我們的目標是每毫升 1 微克。

If you look at where most therapeutic antibodies live in terms of concentrations, if you pull the FDA label for REMICADE, the trough levels are between 0.5 per microgram per mL and about 6 microgram per mL.

如果您查看大多數治療性抗體的濃度，如果您拉出 REMICADE 的 FDA 標籤，您會發現谷值水平在每毫升 0.5 微克到每毫升 6 微克之間。

So it's within the range of what monoclonal antibodies have achieved for therapeutic levels from many indications.

因此，它在單克隆抗體針對許多適應症所達到的治療水平的範圍內。

And our next question comes from Cory Kasimov from JPMorgan.

我們的下一個問題來自摩根大通的科里·卡西莫夫。

I have 2 of them for you as well.

我也有 2 個給你。

So first one is I'm curious how this RSV decision changes how you're thinking about your CMV program, if at all?

首先，我很好奇 RSV 的決定會如何改變您對 CMV 計劃的看法（如果有的話）？

And maybe what the latest in terms of time lines for when we should expect data from that fourth dosing cohort from CMV?

也許我們應該期待來自 CMV 第四個給藥組的數據的最新時間線是什麼？

And then I have one follow-up.

然後我有一個後續行動。

Yes, so this is Tal.

是的，這就是塔爾。

It does not actually change, in my view, one iota how we think of CMV or what we're doing about CMV.

在我看來，它實際上並沒有改變我們對 CMV 的看法或我們對 CMV 所做的事情有絲毫改變。

I think if you look at the totality of our data, to date, we've shown a pretty consistent safety and tolerability profile across the 1,000 or so healthy volunteers that have been dosed across the various programs.

我認為，如果你看看我們迄今為止的全部數據，我們已經在 1,000 名左右的健康志願者中展示了相當一致的安全性和耐受性概況，這些志願者在各個項目中接受了給藥。

And so now it's about figuring out the best vaccine and the best dose for any given application.

因此，現在的重點是找出針對任何特定應用的最佳疫苗和最佳劑量。

In that regard, CMV -- the dose for CMV and the activity for CMV needs to be defined in the context of a CMV clinical trial.

在這方面，CMV——CMV 的劑量和 CMV 的活性需要在 CMV 臨床試驗的背景下定義。

I can't give you a forward guidance.

我無法給你前瞻性的指導。

Obviously, clinical trials are at the mercy of a lot of external factors, but if you look at our past performance and if you see where this trial is, you can sort of connect the dots.

顯然，臨床試驗受到許多外部因素的影響，但如果你看看我們過去的表現，如果你看到這個試驗的情況，你就可以把這些點聯繫起來。

And we're at the fourth dose level here.

我們現在處於第四劑量水平。

The goal with this vaccine is really to -- since it's a Phase I and you're dose escalating, we want to make sure, we're getting a good sense of what would be a tolerable profile to take forward.

這種疫苗的目標實際上是——因為它是第一階段並且劑量正在增加，我們希望確保我們能夠很好地了解什麼是可以容忍的情況，可以繼續推進。

And so as we continue to dose escalate, at some point, we will say, okay, we think we've reached the bar for what should be tolerable.

因此，當我們繼續增加劑量時，在某個時候，我們會說，好吧，我們認為我們已經達到了可以容忍的標準。

That's how you defined it in the Phase I; at which point, we'll wait and make sure that we understand the immunogenicity and then we'll show the data.

這就是你在第一階段的定義；此時，我們將等待並確保我們了解免疫原性，然後我們將顯示數據。

Okay.

好的。

And then, the follow-up question is on MMA and curious when we should expect the first patient to be dosed in that program?

然後，後續問題是關於 MMA 的，我們很好奇我們什麼時候應該期望第一個患者在該計劃中接受給藥？

And can you just kind of give maybe a little overview on what that dose escalation strategy might be there?

您能否簡單介紹一下劑量遞增策略？

Yes.

是的。

So as we said, we're -- the IND has been open for a couple of months now.

正如我們所說，IND 已經開放幾個月了。

It takes you time to talk to sites, initiate the sites.

您需要時間與站點交談、啟動站點。

The first cohort here following discussions with regulators is going to be adolescents, aged 12 to 18.

與監管機構討論後的第一批人群將是 12 至 18 歲的青少年。

So obviously, we're in active discussion with the sites to get them initiated, get the study ongoing.

顯然，我們正在與這些網站進行積極的討論，以啟動它們，讓研究繼續進行。

And at the same time, talking to the investigators and even the patient advocacy groups here to try and identify the patients.

與此同時，與這裡的調查人員甚至患者權益團體交談，試圖識別患者的身份。

In terms of the dosing regimen that you asked, this is sort of a traditional dose exploration.

就您所問的給藥方案而言，這是一種傳統的劑量探索。

We're going in from the very first dose in this disease at a dose that can be effective.

我們從治療這種疾病的第一劑開始就以有效的劑量進行治療。

It's one of the requirements to do a pediatric development.

這是進行兒科發育的要求之一。

And so even at the initial starting dose, which is 0.2 milligrams per kilogram, we think we -- there's an opportunity to have benefit and we'll dose escalate from there based on the totality of tolerability and what we see in terms of biomarker effect.

因此，即使在最初的起始劑量（每公斤0.2 毫克）下，我們也認為我們有機會獲益，我們將根據總體耐受性和我們在生物標誌物效應方面看到的情況，從那裡逐步增加劑量。

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

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

Thanks for hosting us yesterday up in Cambridge, that was really interesting.

感謝您昨天在劍橋接待我們，這真的很有趣。

I want to pick up on Cory's first question just with respect to CMV development path, and maybe you can kind of outline sort of where you would expect to take the Phase I data sets and what next studies would be?

我想回答 Cory 關於 CMV 開發路徑的第一個問題，也許您可​​以概述一下您希望在哪裡獲取第一階段數據集以及下一步的研究是什麼？

And then I just have one quick follow-up, please.

請我快速跟進一下。

So I think the Phase I -- the goal is to demonstrate obviously tolerability, safety and immunogenicity.

所以我認為第一階段的目標是證明明顯的耐受性、安全性和免疫原性。

In our case, the critical pieces to be able to demonstrate the immunogenicity against both components of this vaccine.

在我們的案例中，關鍵部分是能夠證明針對該疫苗的兩種成分的免疫原性。

As you would recall, we both have a complex pentameric protein here, which I think is a unique feature you can do with mRNA and against gB, so we need to figure that out.

你可能還記得，我們這裡都有一個複雜的五聚體蛋白，我認為這是你可以用 mRNA 和針對 gB 實現的獨特功能，所以我們需要弄清楚這一點。

Now in terms of a full development path, I think there is work ahead of us to talk to FDA and other regulators to understand this is obviously a very high unmet need, but it is an unmet need within a context that's obviously challenging to develop, which is trying to prevent maternal transmission to babies in utero is what we're trying to achieve here at the end of the day.

現在就完整的開發路徑而言，我認為我們還需要與FDA 和其他監管機構交談，以了解這顯然是一個非常高的未滿足需求，但在開發顯然具有挑戰性的背景下，這是一個未滿足的需求，試圖阻止母體傳播給子宮內的嬰兒，這就是我們最終想要實現的目標。

Getting there is not simple.

到達那裡並不簡單。

Over the years, there have been various discussions of other companies with the FDA, so there is a good body of precedent for what full development looks like.

多年來，其他公司與 FDA 進行了各種討論，因此對於全面開發的情況有很多先例。

We're just starting down the path of those conversations.

我們才剛剛開始進行這些對話。

I will say that the effort on our side is led by Wellington Sun as you may recall, he was the prior Division Director for Vaccines for FDA for the past decade before joining our team.

我想說的是，我們這邊的工作是由 Wellington Sun 領導的，您可能還記得，在加入我們團隊之前，他在過去十年中擔任 FDA 疫苗部門主管。

So he is very busy these days actually putting this together, discussing with other experts in the field and planning on that next set of conversations to understand what that full development path would look like.

因此，他這些天非常忙，實際上將這些內容放在一起，與該領域的其他專家進行討論，併計劃下一組對話，以了解完整的開發路徑會是什麼樣子。

Great.

偉大的。

That's super helpful.

這非常有幫助。

And then one more for you Tal, if I may.

如果可以的話，再給你一份塔爾。

Just with respect to the triplet program for IL, for cancer, so I was pleased to see that you guys are expanding to the second dose.

就 IL 和癌症的三聯計劃而言，我很高興看到你們正在擴大到第二劑。

I think this thing is going to really carry a big hammer and safety is going to be the one of the primary focus areas.

我認為這件事將真正帶來重錘，安全將成為主要關注領域之一。

Was there anything you saw to date that gives you any pause there?

迄今為止，您是否看到過任何讓您停頓的事情？

Or how is that looking from an early standpoint from a safety side?

或者從安全方面的早期角度來看，情況如何？

So look, it's hard for me to comment on a trial that's in progress.

所以看，我很難對正在進行的審判發表評論。

The data continues to come in, and we're obviously evaluating it on an ongoing basis.

數據不斷出現，我們顯然正在持續對其進行評估。

I can tell you that we're at the second dose level.

我可以告訴你，我們處於第二劑量水平。

As a reminder, for OX40 ligand alone, for the membrane protein, we got up to 8-milligram, which was the intended dose and that seemed to be tolerated well.

提醒一下，對於單獨的 OX40 配體，對於膜蛋白，我們達到了 8 毫克，這是預期劑量，而且似乎耐受性良好。

So in terms of the contribution of OX40 ligand itself and the lipids nanoparticle delivery technology, I'm pretty comfortable with their tolerability profile.

因此，就 OX40 配體本身的貢獻和脂質納米顆粒遞送技術而言，我對它們的耐受性非常滿意。

I think your question is correct with locally secreted cytokines, do you get to a level that is worrisome?

我認為你的問題對於局部分泌的細胞因子是正確的，你是否達到了令人擔憂的水平？

I don't know yet.

我還不知道。

I would point that the preclinical data in totality was pretty supportive of going to much higher doses.

我想說的是，臨床前數據總體上非常支持使用更高的劑量。

I think that's the unique ability of mRNA to set up this local paracrine effect within the tumor with minimal spillover into the blood.

我認為這就是 mRNA 的獨特能力，它可以在腫瘤內建立這種局部旁分泌效應，同時將溢出到血液中的情況降至最低。

These are obviously things we'll measure, so we will be looking at the expression of these proteins, both in the tumors and systemically to see if they're detectable.

這些顯然是我們要測量的東西，所以我們將觀察這些蛋白質在腫瘤中和全身的表達，看看它們是否可以檢測到。

We will be looking at the typical safety parameters, [safety] labs, et cetera.

我們將研究典型的安全參數、[安全]實驗室等。

It's frankly, too early to say.

坦率地說，現在說還為時過早。

And our next question comes from Alan Carr of Needham & Company.

我們的下一個問題來自 Needham & Company 的艾倫·卡爾 (Alan Carr)。

I wish you could -- I'm hoping you can tell us a little bit more about some of these rare disease programs that -- or preclinical programs that you presented just recently.

我希望你能——我希望你能告訴我們更多關於一些罕見疾病項目的信息——或者你最近提出的臨床前項目。

It looks like a bit of a shotgun strategy in terms of the number that you have running in parallel, how do you decide which ones to bring forward?

就並行運行的數量而言，這看起來有點像霰彈槍策略，您如何決定將哪些項目提前？

And maybe give us a sense of expectation in terms of when these might move forward in the clinic?

也許讓我們對這些何時能在臨床上取得進展感到期待？

And then the second one, I'm wondering if you can elaborate a bit more about this proprietary formulation developed by Merck for 1172?

然後是第二個問題，我想知道您是否可以詳細說明一下默克公司為 1172 開發的這種專有配方？

To what extent do you, I guess, work with Merck on developing new delivery formulations for in both those specific programs?

我想，您在多大程度上與默克公司合作，為這兩個特定項目開發新的給藥配方？

And how do they -- with Merck and then they translate to other programs that are not licensed during collaboration with Merck?

他們如何與默克公司合作，然後將其轉化為在與默克公司合作期間未獲得許可的其他程序？

Sure.

當然。

So the 2 questions.

所以這兩個問題。

So first on the ASGCT abstracts, 5 of which were presented to a wide range of academic collaborators and institutions, as you saw.

首先是 ASGCT 摘要，正如您所看到的，其中 5 份摘要已提交給廣泛的學術合作者和機構。

We do have a very active research collaborations with academia across a very wide range of rare diseases.

我們確實與學術界在廣泛的罕見疾病領域開展了非常積極的研究合作。

What you saw was a sampling of that activity, but it was ready for presentation by many of the academic labs.

您看到的是該活動的樣本，但它已準備好供許多學術實驗室演示。

By participating with those folks, we absolutely commit to them being able to present that data at the appropriate fora as well as publish it.

通過與這些人一起參與，我們絕對致力於讓他們能夠在適當的論壇上展示並發布這些數據。

And so you will see a steady flow of those sorts of things, that doesn't necessarily translate into our portfolio strategy or programs that we're taking forward into development.

因此，你會看到這類事情的穩定流動，這並不一定會轉化為我們的投資組合戰略或我們正在推進的開發計劃。

I'll point to our own publication record there, even in the last couple of years, there was a number of programs that we published in high-impact journals that are not currently in our development pipeline.

我將指出我們自己的出版記錄，即使在過去幾年中，我們在高影響力期刊上發表的許多程序目前尚未納入我們的開發流程中。

What we choose to take into development goes through a different series of filters in terms of prioritization as well as our view on unmet need and developability.

我們選擇開發的內容會根據優先級以及我們對未滿足需求和可開發性的看法經過一系列不同的過濾。

So I can't comment on whether or not you should expect those things to be translating forward, and in fact, I would only say that you should expect to continue to see a large amount of that activity both in publication and presentation collaborations with academia.

因此，我無法評論您是否應該期望這些事情能夠向前發展，事實上，我只會說您應該期望在與學術界的出版和演示合作中繼續看到大量此類活動。

Onto the 1172 delivery vehicle, so we -- obviously, we've had a multiyear collaboration with Merck where we do talk a lot about things we're learning to enable the best development of the programs we're partnering with on them, including the vaccines like RSV.

在 1172 運載工具上，顯然，我們與默克進行了多年的合作，我們確實談論了很多我們正在學習的事情，以實現我們正在合作的項目的最佳開發，包括RSV 等疫苗。

We -- I can't comment specifically on the improvements that went into the 1172 formulations that Merck was developing, but -- or is developing, but obviously we published last year in a paper on our website, Tasset et al, some of the deficiencies with the legacy lipid nanoparticle formulations in terms of local tolerability in the vaccine context.

我們 - 我無法具體評論默克正在開發的 1172 配方的改進，但是 - 或正在開發，但顯然我們去年在我們的網站上發表了一篇論文，Tasset 等人，其中一些傳統脂質納米顆粒製劑在疫苗局部耐受性方面存在缺陷。

That underpinned a lot of our efforts to -- several years ago to develop our own proprietary lipid nanoparticle delivery technologies that are actually already in programs like CMV and hMPV PIV.

這支撐了我們幾年前開發自己專有的脂質納米顆粒遞送技術的大量努力，這些技術實際上已經應用於 CMV 和 hMPV PIV 等項目中。

RSV had started before that as an effort and so as we shared that data with Merck long before we published it, they made their own determinations about what that might mean for that development program.

RSV 在此之前就已經開始了一項努力，因此當我們在發布數據之前很久就與默克分享了這些數據時，他們就這對該開發計劃可能意味著什麼做出了自己的決定。

And as I said, I'll let them, at the appropriate time, talk about any improvements in specifics, but obviously, they are aware of all of work together.

正如我所說，我會讓他們在適當的時候談論具體的任何改進，但顯然，他們知道所有的工作都是一起進行的。

Now we do share information back and forth.

現在我們確實來回共享信息。

I think part of your question was do we collaborate on these things, and obviously, we do.

我認為你的部分問題是我們是否在這些事情上進行合作，顯然，我們確實合作了。

We were sharing that information with Merck long before the publication, and as they make improvements and step-forwards in formulation then that becomes a 2-way street, and so we're excited about it.

早在出版之前，我們就與默克分享了這些信息，隨著他們在配方方面的改進和進步，這就變成了一條雙向路，所以我們對此感到興奮。

And our next question comes from Geoff Meacham of Barclays.

我們的下一個問題來自巴克萊銀行的傑夫·米查姆。

For the new GSP program, the disease ideology is pretty complicated with multiple organs involved.

對於新的普惠制計劃來說，疾病意識形態相當複雜，涉及多個器官。

I guess the question is, just help us with how you're thinking about the regulatory path down the road post proof of concept?

我想問題是，請幫助我們了解一下概念驗證後的監管路徑？

I imagine there's been some discussion of endpoints already.

我想已經有一些關於端點的討論了。

And I have a follow-up.

我有一個後續行動。

Geoff, this is Tal.

傑夫，這是塔爾。

It's a great question.

這是一個很好的問題。

This disease is a different one, as you rightly point out.

正如您正確指出的那樣，這種疾病是一種不同的疾病。

The unmet need here is -- it's not just the multiple organs that are affected, if you think about the patient experience and the quality of life, it's the frequent feeding at night, but if you actually meet one of these patients, which I had the opportunity to sit down, when I sit for a meeting for 2 hours, I typically take a cup of coffee.

這裡未滿足的需求是——這不僅僅是多個器官受到影響，如果你考慮到病人的經歷和生活質量，那就是夜間頻繁餵食，但如果你真的遇到了其中一位病人，我曾經遇到過坐下來的機會，當我開會坐兩個小時時，我通常會喝杯咖啡。

A GSD1a patient who sits for a 2-hour meeting needs to have a cup of cornstarch that they're drinking.

參加 2 小時會議的 GSD1a 患者需要喝一杯他們正在喝的玉米澱粉。

And if you think about that day in, day out your entire life, there's obviously a high unmet need there that's manifest in many dimensions.

如果你日復一日地思考你的一生，顯然有一個很高的未滿足的需求，這在很多方面都有體現。

Now to your point about regulatory path and endpoints, I think it's still early days.

現在就您關於監管路徑和終點的觀點而言，我認為現在還為時過早。

This is just the declaration of our intent in the development candidate, there's work ahead of us.

這只是我們開發候選者意圖的聲明，我們還有很多工作要做。

We have to go talk to the agency.

我們必須去跟該機構談談。

We have to go figure out the strategy for the Phase I first and then we have to understand what is going to be the development path to bring and demonstrate that we can actually impact not just the basic biology of these diseases, as you've shown quite remarkably, I think in the mouse model, but actually, how do we demonstrate that we're able to address all those manifold manifestations of this disease spanning from the biochemistry all through the quality of life, preventing relatively rare but very severe events, but at the same time actually changing their day-to-day quality of life in a much more consistent fashion.

我們必須首先找出第一階段的策略，然後我們必須了解將帶來什麼發展路徑，並證明我們實際上不僅可以影響這些疾病的基本生物學，正如您所展示的那樣我認為在小鼠模型中非常值得注意，但實際上，我們如何證明我們能夠解決這種疾病的所有這些多種表現，從生物化學到生活質量，預防相對罕見但非常嚴重的事件，但同時實際上以更加一致的方式改變了他們的日常生活質量。

That's a lot of work that's still ahead of us.

我們還有很多工作要做。

Got you.

明白你了。

Okay.

好的。

That's helpful.

這很有幫助。

And then, on the cancer vaccine and the IO programs, I know you're in an enrollment ramp at this point, but maybe can you speak to whether we'll see any clinical updates at the upcoming ASCO meeting?

然後，關於癌症疫苗和 IO 項目，我知道您目前正處於招生​​階段，但您能否談談我們是否會在即將召開的 ASCO 會議上看到任何臨床更新？

So the -- you know it's a medical meeting.

所以——你知道這是一次醫學會議。

You like to show the data that you have, I'll point to you that the -- to the abstracts once they will be live I think in a couple of weeks, so they will describe the contents of the data that we will be sharing there.

你想展示你擁有的數據，我會向你指出，我想幾週後，一旦摘要發布，它們將描述我們將共享的數據的內容那裡。

(Operator Instructions) Our next question comes from Ying Huang of Bank of America.

（操作員指令）我們的下一個問題來自美國銀行的黃英。

I want to ask about the GSD1a program.

我想詢問有關GSD1a 計劃的問題。

First of all, I guess, now we have 5 rare disease programs in the pipeline.

首先，我想，現在我們有 5 個罕見疾病項目正在醞釀之中。

Does that suggest an increasing focus on this modality compared to others?

這是否表明與其他方式相比，人們越來越關注這種方式？

Secondly, there is a competitor which is conducting a trial in gene therapy for this disease specifically.

其次，有一個競爭對手正在專門針對這種疾病進行基因治療試驗。

Can you talk about maybe pros and cons versus the mRNA approach?

您能談談 mRNA 方法的優缺點嗎？

And given the data we obtained recently from (inaudible), what do you think you can improve on?

鑑於我們最近獲得的數據（聽不清），您認為您可以改進哪些方面？

This is Stéphane, I am going to take your first question and Stephen will be talk about gene therapy.

我是斯蒂芬，我將回答你的第一個問題，斯蒂芬將談論基因治療。

So as we indicated since early 2018, rare disease is an important point of focus for the company, obviously because of the unmet medical need, because of a quick path to approval, and also because what we believe is a lower biology risk against some of the things we're trying to do.

因此，正如我們自2018 年初以來所指出的那樣，罕見疾病是公司的一個重要關注點，顯然是因為未得到滿足的醫療需求，因為獲得批准的快速途徑，也因為我們認為針對某些疾病的生物學風險較低。我們正在嘗試做的事情。

So as you know, as we beat the pipeline of the company, as I said in my introduction remarks, we focus very much on managing risk.

如您所知，正如我在介紹中所說，當我們擊敗公司的管道時，我們非常注重管理風險。

And so the way we think about our pipeline now in development is, we have some very interesting vaccine in infectious disease that got a big unmet medical need that I think we have a relevant approach to function in addition to be able to help a lot of people.

因此，我們對目前正在開發的管道的看法是，我們有一些非常有趣的傳染病疫苗，這些疫苗有很大的未滿足的醫療需求，我認為我們除了能夠幫助很多人之外，還有一種相關的運作方法。人們。

With 5 other programs now we think we have a nice portfolio of IO and what we were looking for is great execution in the clinic to see what we can do for patients with those programs.

現在有了其他 5 個項目，我們認為我們擁有了一個很好的 IO 組合，我們所尋求的是在臨床上的出色執行，看看我們可以通過這些項目為患者做些什麼。

And given the more "straightforward" biology of rare disease were clearly missing instruction for the DNA, and as you have seen in a lot of publication work that we have done, there's very exciting preclinical model data.

鑑於罕見疾病的更“直接”生物學顯然缺少 DNA 指導，正如您在我們所做的大量出版物工作中看到的那樣，有非常令人興奮的臨床前模型數據。

We really want to focus on rare diseases and this is consistent with the strategy we are outlining now and 1.5 years ago.

我們確實希望關注罕見疾病，這與我們現在和 1.5 年前製定的戰略是一致的。

And also what you saw at the ASGCT a few weeks ago, there's a lot of work going on there.

正如您幾週前在 ASGCT 上看到的那樣，那裡正在進行大量工作。

This is a very important area for the company.

這對公司來說是一個非常重要的領域。

Yes.

是的。

And on GSD1a, and gene therapy specifically -- or generally, we -- starting with mRNA, our focus is on dose-dependent pharmacology.

對於 GSD1a 和基因治療，特別是——或者一般來說，我們——從 mRNA 開始，我們的重點是劑量依賴性藥理學。

I think the defining feature of our platform is our ability to have predictable dose-dependent pharmacology.

我認為我們平台的決定性特徵是我們具有可預測的劑量依賴性藥理學的能力。

You give a dose today, you get a response.

您今天服用一劑，就會得到反應。

You give it next week, you get the same response.

你下週再給它，你會得到同樣的回應。

If you need a more response tomorrow, I give twice the dose, you should expect to get twice the response and that's what we mean by sort of dose-dependent pharmacology functions like a traditional drug.

如果你明天需要更多的反應，我會給予兩倍的劑量，你應該期望得到兩倍的反應，這就是我們所說的像傳統藥物一樣的劑量依賴性藥理學功能。

We focus a lot of our rare disease efforts in metabolic diseases where you would expect the needs of the patient based on metabolism will change over time.

我們將許多罕見疾病工作重點放在代謝疾病上，您預計患者基於代謝的需求會隨著時間的推移而改變。

Sometimes in a week, sometimes over years as they age.

有時是一周，有時是幾年，隨著年齡的增長。

And in particular, as they're growing and young can be highly dynamic.

特別是，隨著他們的成長，年輕人可能會充滿活力。

And so we focus on looking at the disease like GSD1a, mRNA is another example of this, where we are expecting to need to titrate to the dose response that's desirable to manage that disease.

因此，我們專注於研究像 GSD1a 這樣的疾病，mRNA 是另一個例子，我們預計需要滴定到控制該疾病所需的劑量反應。

Now there are, as you mentioned, a gene therapy approach going after GSD1a as we speak and we really don't view those as necessarily competitive.

正如您所提到的，現在有一種針對 GSD1a 的基因治療方法，我們確實不認為這些方法具有一定的競爭力。

In fact, we think these are different tools that physicians will use hopefully in combination for different purposes to help patients manage this disease.

事實上，我們認為醫生將有希望將這些不同的工具結合起來用於不同的目的，以幫助患者控制這種疾病。

We can easily imagine a world where sort of analogous to insulin is sort of basal long-acting forms, but you're still managing the disease day in, day out with -- by testing blood glucose for week in, week out by controlling for it.

我們可以很容易地想像一個世界，其中類似於胰島素的基礎長效形式，但你仍然日復一日地控制疾病——通過控制一周又一周的血糖它。

That would give, frankly, the physician we hope that -- personally, I would hope that they're successful and we're successful because more tools for clinicians as they are treating patients will be a great thing.

坦率地說，這將為我們希望的醫生提供——就我個人而言，我希望他們成功，我們也成功，因為臨床醫生在治療患者時擁有更多工具將是一件偉大的事情。

So we don't necessarily view it as competitive.

所以我們不一定認為它具有競爭力。

We view it as adjunctive and we're focusing on different areas of pharmacology.

我們將其視為輔助手段，並且專注於藥理學的不同領域。

And I'm not showing any further questions at this time.

目前我不會提出任何進一步的問題。

I would now like to turn the call back over to Stéphane Bancel for any further remarks.

我現在想將電話轉回 Stéphane Bancel，以徵求進一步意見。

Well, thank you very much for joining us today and for your questions.

非常感謝您今天加入我們並提出問題。

We look forward to talking and to seeing many of you in the coming weeks, including at the ASCO around the PCV posters.

我們期待在未來幾週內與你們交談並見到你們，包括在 ASCO 上圍繞 PCV 海報進行討論。

Have a great day.

祝你有美好的一天。

Thank you.

謝謝。

Ladies and gentlemen, thank you for participating in today's conference.

女士們、先生們，感謝你們參加今天的會議。

This does conclude today's program and you may all disconnect.

今天的節目到此結束，大家可以斷線了。

Everyone, have a wonderful day.

祝大家度過美好的一天。