Arrowhead Pharmaceuticals Inc (ARWR) 2022 Q3 法說會逐字稿

Ladies and gentlemen, welcome to the Arrowhead Pharmaceuticals Conference Call. (Operator Instructions)

女士們，先生們，歡迎來到 Arrowhead Pharmaceuticals 電話會議。 （操作員說明）

I will now hand the conference over to Vincent Anzalone, Vice President of Investor Relations for Arrowhead. Please go ahead, Vince.

我現在將會議交給 Arrowhead 投資者關係副總裁 Vincent Anzalone。請繼續，文斯。

Good afternoon, everyone. Thank you for joining us today to discuss Arrowhead's results for its fiscal 2022 third quarter ended June 30, 2022.

大家下午好。感謝您今天加入我們，討論 Arrowhead 截至 2022 年 6 月 30 日的 2022 財年第三季度業績。

With us today from management are President and CEO, Dr. Christopher Anzalone, who will provide an overview of the quarter; Dr. Javier San Martin, our Chief Medical Officer, who will provide an update on our mid-and later-stage clinical pipeline; Dr. James Hamilton, our Senior Vice President of Discovery and Translational Medicine, who will provide an update on our earlier stage programs; and Ken Myszkowski, our Chief Financial Officer, who will give a review of the financials. In addition, Tracie Oliver, our newly appointed Chief Commercial Officer and Patrick O'Brien, who was recently promoted to Chief Operating Officer and General Counsel, will both be available during the Q&A portion of the call.

今天與我們一起來自管理層的是總裁兼首席執行官 Christopher Anzalone 博士，他將提供本季度的概述；我們的首席醫療官 Javier San Martin 博士將提供我們中後期臨床管線的最新信息；我們的發現和轉化醫學高級副總裁 James Hamilton 博士將介紹我們早期項目的最新情況；和我們的首席財務官 Ken Myszkowski，他將對財務狀況進行審查。此外，我們新任命的首席商務官 Tracie Oliver 和最近晉升為首席運營官兼總法律顧問的 Patrick O'Brien 都將在電話問答環節出席。

Before we begin, I would like to remind you that comments made during today's call contain certain forward-looking statements within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934. All statements, other than statements of historical facts, are forward-looking statements and are subject to numerous risks and uncertainties that could cause actual results to mature to differ materially from those expressed in any forward-looking statements. For further details concerning these risks and uncertainties, please refer to our SEC filings, including our most recent Annual Report on Form 10-K and our Quarterly Reports on Form 10-Q.

在我們開始之前，我想提醒您，在今天的電話會議中發表的評論包含 1933 年證券法第 27A 條和 1934 年證券交易法第 21E 條含義內的某些前瞻性陳述。所有陳述，除了歷史事實的陳述是前瞻性陳述，受眾多風險和不確定性的影響，這些風險和不確定性可能導致實際結果與任何前瞻性陳述中表達的結果大不相同。有關這些風險和不確定性的更多詳細信息，請參閱我們向美國證券交易委員會提交的文件，包括我們最近的 10-K 表格年度報告和 10-Q 表格季度報告。

With that said, I'd like to turn the call over to Christopher Anzalone, President and CEO of the company. Chris?

話雖如此，我想把電話轉給公司總裁兼首席執行官克里斯托弗安扎隆。克里斯？

Thanks, Vince. Good afternoon, everyone, and thank you for joining us today.

謝謝，文斯。大家下午好，感謝您今天加入我們。

Before I cover key events and progress during the previous quarter, I want to talk about some recent management additions that make us a stronger company today and importantly, as we grow into a vertically integrated, commercial stage pharmaceutical company. We're currently conducting one Phase III study for a wholly-owned drug candidate, and I expect us to begin one or 2 additional Phase III studies next year. As such, there are important strategic decisions we need to begin considering that will affect how we ultimately commercialize these drug candidates.

在我介紹上一季度的關鍵事件和進展之前，我想談談最近的一些管理人員增加，這些增加使我們今天成為一家更強大的公司，重要的是，隨著我們成長為一家垂直整合的商業階段製藥公司。我們目前正在對一種全資候選藥物進行一項 III 期研究，我預計明年我們將開始另外一項或兩項 III 期研究。因此，我們需要開始考慮一些重要的戰略決策，這些決策將影響我們最終將這些候選藥物商業化的方式。

We are thrilled to welcome Tracie Oliver as our Chief Commercial Officer to start to build out our commercial infrastructure and more immediately contribute to the planning of our late-stage programs to ensure that our future commercial requirements are harmonized with clinical datasets and ultimate drug labels.

我們很高興地歡迎 Tracie Oliver 擔任我們的首席商務官，開始構建我們的商業基礎設施，並更直接地為我們後期項目的規劃做出貢獻，以確保我們未來的商業需求與臨床數據集和最終藥物標籤相協調。

Tracie has over 30 years of global experience in the biopharmaceutical industry, leading both R&D and commercial organizations. Prior to joining Arrowhead, she had our own consulting practice, focused on providing guidance to small, emerging commercial stage biotech companies on the proper strategy, timelines, methods and ultimately the build-out of new commercial organizations.

Tracie 在生物製藥行業擁有超過 30 年的全球經驗，領導著研發和商業組織。在加入 Arrowhead 之前，她擁有我們自己的諮詢業務，專注於就適當的戰略、時間表、方法以及最終建立新的商業組織向小型、新興商業階段的生物技術公司提供指導。

Those skills and experience are critical to Arrowhead as we look to take the next steps in our growth as a company. Prior to her consulting business, Tracie was with Shire Pharmaceuticals through the acquisition of Baxalta and was Global Head of New Product Planning and Device Strategy. Prior to that, she held several commercial roles at Baxter and Baxalta, including establishing a new oncology franchise and leading the North America Immunology Business Unit and Autoimmune Franchise.

這些技能和經驗對 Arrowhead 至關重要，因為我們希望在公司發展過程中採取下一步行動。在從事諮詢業務之前，Tracie 在收購 Baxalta 後供職於 Shire Pharmaceuticals，並擔任新產品規劃和設備戰略的全球主管。在此之前，她在 Baxter 和 Baxalta 擔任過多個商業職務，包括建立新的腫瘤專營權以及領導北美免疫學業務部門和自身免疫專營權。

Tracie began her career in the biopharmaceutical industry with Johnson & Johnson and served as Head of Ortho Biotech Nephrology Business Unit in Canada, Ortho McNeil Neurologics, and McNeil Pediatrics in the USA. As we continue this type of growth in personnel and departments, we need to be more deliberate in our drive to continue operational excellence. There can be a tendency toward an inverse relationship between the size of an organization and its ability to operate efficiently, creatively and rapidly. It is important to us that we maintain our operational excellence as we grow, and Patrick O'Brien, our General Counsel, will now also take on the role of Chief Operating Officer to help ensure this.

Tracie 的職業生涯始於強生公司的生物製藥行業，並曾擔任加拿大 Ortho Biotech 腎髒病學業務部、美國 Ortho McNeil Neurologics 和 McNeil Pediatrics 的負責人。隨著我們在人員和部門方面繼續這種類型的增長，我們需要更加謹慎地推動繼續卓越運營。一個組織的規模與其高效、創造性和快速運作的能力之間可能存在一種反比關係。隨著我們的成長，保持卓越運營對我們來說很重要，我們的總法律顧問 Patrick O'Brien 現在也將擔任首席運營官一職，以幫助確保這一點。

I will now move on to review some of our recent progress. We view setbacks as a normal part of innovation and if we can learn something from them, they may serve as an investment in the future. The recent progress we've made in our pulmonary platform is a good example of this and a powerful illustration of how fast Arrowhead can move. As you know, our first candidate in the clinic using the pulmonary targeted TRiM platform was ARO-ENaC for the treatment of cystic fibrosis.

我現在將繼續回顧我們最近的一些進展。我們將挫折視為創新的正常組成部分，如果我們能從中學到一些東西，它們可能會成為對未來的投資。我們最近在肺平台上取得的進展就是一個很好的例子，也是 Arrowhead 移動速度的有力例證。如您所知，我們在臨床上使用肺部靶向 TRiM 平台的第一個候選藥物是用於治療囊性纖維化的 ARO-ENaC。

Last year, we decided to pause enrollment in the ARO-ENaC first-in-human clinical study, as we further investigated some findings from a non-clinical toxicology study that suggested some local lung inflammation after chronic treatment at certain high doses. Many open questions remained. James will speak to what we learned in more detail later in the call. But after extensive investigation, consultation with internal and external toxicology experts and additional studies, it appears that findings were consistent with what is called lung macrophage overload. Essentially, the volume of material, not necessarily the specific drug or target was swamping the lungs' clearance mechanisms and causing an inflammatory response.

去年，我們決定暫停 ARO-ENaC 首次人體臨床研究的註冊，因為我們進一步調查了一項非臨床毒理學研究的一些發現，這些研究表明在某些高劑量的慢性治療後會出現局部肺部炎症。許多懸而未決的問題仍然存在。詹姆斯將在稍後的電話會議中更詳細地講述我們了解到的內容。但經過廣泛調查、諮詢內部和外部毒理學專家以及其他研究後，這些發現似乎與所謂的肺巨噬細胞超負荷一致。從本質上講，物質的體積，不一定是特定的藥物或靶標，正在淹沒肺部的清除機制並引起炎症反應。

So the clear way to move forward is to understand the amount of material that triggers this phenomenon and develop more potent, longer-acting candidates to stay below the assumed cumulative dose threshold. I believe we have done that for our next-generation candidates, ARO-RAGE and ARO-MUC5AC, resulting in 3 important improvements.

因此，向前推進的明確方法是了解引發這種現象的物質的數量，並開發更有效、作用時間更長的候選藥物，以保持在假定的累積劑量閾值以下。我相信我們已經為我們的下一代候選藥物 ARO-RAGE 和 ARO-MUC5AC 做到了這一點，從而帶來了 3 項重要的改進。

First, we think we can now achieve better knockdown with less exposure. Second, we think we can give a single dose as opposed to our previous need to dose on 3 consecutive days. And third, we believe we can now stretch the dose interval substantially. For example, ARO-ENaC was going to be dosed 3 times -- I'm sorry, 3 times, every 2 or 3 weeks and ARO-RAGE has duration that potentially lasts multiple months after a single dose.

首先，我們認為我們現在可以用更少的暴露實現更好的擊倒。其次，我們認為我們可以給予單劑，而不是之前需要連續 3 天給藥。第三，我們相信我們現在可以大大延長劑量間隔。例如，ARO-ENaC 將給藥 3 次——對不起，每 2 或 3 週給藥 3 次，而 ARO-RAGE 的持續時間可能在單次給藥後持續數月。

Each of these improvements are important on their own. But together, we believe they dramatically changed the profile of our next-generation pulmonary candidates. So where are we now? The work and lessons that went into this happened over an extended period, culminating this quarter -- this last quarter in 2 important events. We held a pulmonary R&D Day to go over our findings and present non-clinical data from our next-generation candidates ARO-RAGE and ARO-MUC5AC. And then shortly after, we began dosing patients in 2 clinical studies. As I said, I think this is a great example of what Arrowhead is capable of. We went from pausing enrollment of the ARO-ENaC clinical program to initiating clinical studies and dosing human subjects with next-generation candidates that potentially have dramatically improved profiles in about 12 months.

這些改進中的每一項本身都很重要。但我們相信，它們共同極大地改變了我們下一代肺部候選人的形象。那麼我們現在在哪裡？這方面的工作和經驗教訓發生在很長一段時間內，在本季度達到高潮——最後一個季度有兩個重要事件。我們舉辦了一個肺部研發日來回顧我們的發現並展示我們的下一代候選藥物 ARO-RAGE 和 ARO-MUC5AC 的非臨床數據。不久之後，我們開始在 2 項臨床研究中對患者進行給藥。正如我所說，我認為這是 Arrowhead 功能的一個很好的例子。我們從暫停 ARO-ENaC 臨床計劃的註冊到啟動臨床研究，並給人類受試者服用下一代候選藥物，這些候選藥物可能在大約 12 個月內顯著改善概況。

There was an enormous amount of work, thoughts, creativity, technology and innovation that enabled this result. The pulmonary TRiM platform is an important expansion of our technology that we expect will help a large number of patients and create a substantial amount of value. But it is just one example of how we are growing our platform. We expect many more going forward.

有大量的工作、思想、創造力、技術和創新促成了這一結果。肺部 TRiM 平台是我們技術的重要擴展，我們預計它將幫助大量患者並創造大量價值。但這只是我們如何發展我們的平台的一個例子。我們期待更多的前進。

Another set of key accomplishments during the quarter relate to execution on our later-stage programs for our cardiometabolic candidates, ARO-APOC3 and ARO-ANG3. Between the 2 candidates, we have 5 active clinical studies that range from ultra-rare disease populations to high-prevalence diseases. The design and execution of clinical studies for diseases on opposite ends of the size spectrum typically have different tactics and require specialized expertise.

本季度的另一組關鍵成就與我們針對心臟代謝候選藥物 ARO-APOC3 和 ARO-ANG3 的後期項目的執行有關。在這 2 名候選人中，我們有 5 項活躍的臨床研究，範圍從極罕見疾病人群到高流行病。針對大小範圍兩端疾病的臨床研究的設計和執行通常採用不同的策略，並且需要專業知識。

I'm happy to report that our clinical development and clinical operations teams have been successfully running all of these studies. On the rare disease side, the Phase III PALISADE study of ARO-APOC3 in patients with FCS is efficiently enrolling patients, and we have worked hard during the quarter to identify and open new countries and sites that should contribute to rapid enrollment of the study.

我很高興地向大家報告，我們的臨床開發和臨床運營團隊已成功開展所有這些研究。在罕見疾病方面，針對 FCS 患者的 ARO-APOC3 III 期 PALISADE 研究正在有效地招募患者，我們在本季度努力尋找和開放新的國家和地點，以促進研究的快速招募。

In addition, during the quarter, we initiated the Phase II GATEWAY study of ARO-ANG3 in patients with HoFH. This study is also enrolling patients efficiently, and we look forward to seeing data in the future. On the high-prevalence disease side, we have 3 ongoing studies. For ARO-APOC3, we are running the SHASTA-2 Phase II study in patients with severe hypertriglyceridemia and the MUIR Phase II study in patients with mixed dyslipidemia. We have executed well on both studies, and we believe we are on schedule for readouts in both studies in 2023.

此外，在本季度，我們啟動了 ARO-ANG3在 HoFH 患者中的 II 期 GATEWAY 研究。這項研究也在有效地招募患者，我們期待在未來看到數據。在高流行病方面，我們正在進行 3 項研究。對於 ARO-APOC3，我們正在進行針對嚴重高甘油三酯血症患者的 SHASTA-2 II 期研究和針對混合性血脂異常患者的 MUIR II 期研究。我們在這兩項研究中都表現良好，我們相信我們將按計劃在 2023 年對這兩項研究進行解讀。

In fact, we recently reached total planned enrollment from MUIR. For ARO-ANG3, there's one high-prevalence disease study, the Phase II ARCHES-2 study in patients with mixed dyslipidemia. This study was fully enrolled earlier in the year and should be complete at the end of the year, and enable a readout in the first half of next year.

事實上，我們最近達到了 MUIR 的計劃招生總數。對於 ARO-ANG3，有一項高患病率疾病研究，即針對混合性血脂異常患者的 II 期 ARCHES-2 研究。該研究已於今年早些時候全部入組，應該會在年底完成，並能夠在明年上半年進行讀數。

The other 2 accomplishments from the recent quarter that I want to highlight are related to corporate goals that aim to maximize the value of our technology over the long term. First, we announced that we broke ground on the construction of a new commercial scale manufacturing facility and received upwards -- receive awards of up to $18.5 million in incentives to invest in the local region and create new jobs. This is an important investment in Arrowhead's future as a vertically integrated commercial stage pharmaceutical company. It helps us control the manufacturing process, both operationally and strategically for our wholly-owned programs and potentially for our partner programs in the future. It potentially reduces the cost of our clinical and commercial drug supply, and importantly helps eliminate any future bottlenecks related to drug manufacturing.

我想強調的最近一個季度的其他 2 項成就與旨在長期最大化我們技術價值的公司目標有關。首先，我們宣布我們破土動工建設一個新的商業規模的製造設施，並獲得了高達 1850 萬美元的獎勵，用於在當地投資和創造新的就業機會。這是 Arrowhead 作為一家垂直整合的商業階段製藥公司未來的一項重要投資。它幫助我們在運營和戰略上控制製造過程，用於我們的全資項目以及未來可能用於我們的合作夥伴項目。它可能會降低我們的臨床和商業藥物供應成本，並且重要的是有助於消除與藥物製造相關的任何未來瓶頸。

Lastly, related to corporate goals, during the last quarter, we also announced that Arrowhead formed Visirna Therapeutics, a joint venture with Vivo Capital, in which Arrowhead is a majority shareholder, to expand the reach of innovative medicines in Greater China. Arrowhead licensed for investigational RNAi therapeutics to Visirna for cardiometabolic diseases in Mainland China, Hong Kong, Macau and Taiwan. Vivo Capital provides $60 million in initial funding to Visirna. This transaction potentially allows us to expand our reach into geographies that are beyond our core focus, while retaining a substantial economic interest.

最後，關於公司目標，在上個季度，我們還宣布 Arrowhead 與 Vivo Capital 成立合資公司 Visirna Therapeutics，Arrowhead 是該公司的大股東，以擴大創新藥物在大中華區的影響力。 Arrowhead 在中國大陸、香港、澳門和台灣獲得 Visirna 研究性 RNAi 療法的許可，用於治療心臟代謝疾病。 Vivo Capital 向 Visirna 提供了 6000 萬美元的初始資金。這項交易有可能使我們能夠將業務範圍擴大到我們核心重點以外的地區，同時保留大量經濟利益。

So in summary, Arrowhead had a productive quarter, where we saw progress in our pipeline of industry-leading RNAi therapeutics, our wide reaching and expanding TRiM technology platform and our corporate goals.

因此，總而言之，Arrowhead 有一個富有成效的季度，我們在行業領先的 RNAi 療法、我們廣泛的影響和擴展的 TRiM 技術平台以及我們的企業目標方面取得了進展。

With that overview, I now like to turn the call over to Dr. Javier San Martin. Javier?

有了這個概述，我現在想把電話轉給 Javier San Martin 博士。哈維爾？

Thank you, Chris, and good afternoon, everyone.

謝謝克里斯，大家下午好。

First, I want to highlight data on the Phase II 2002 study of fazirsiran, formerly called ARO-AAT and TAK-999, presented in July at the EASL, International Liver Congress and published simultaneously in the New England Journal of Medicine. The presentation generated significant enthusiasm within the audience, welcoming positive data to address liver disease with no approved therapy and the validation of a New England Publication.

首先，我想強調 2002 年 fazirsiran II 期研究的數據，這些研究以前稱為 ARO-AAT 和 TAK-999，於 7 月在 EASL 國際肝病大會上發表，並同時發表在新英格蘭醫學雜誌上。演講在聽眾中引起了極大的熱情，歡迎積極的數據來解決未經批准的治療和新英格蘭出版物驗證的肝病。

Fazirsiran is a potential first-in-class investigational RNAi therapy designed to reduce production of a mutant form of alpha-1 antitrypsin protein called Z-AAT as a potential treatment for the rare genetic liver disease associated with alpha-1 antitrypsin deficiency, Z-AAT accumulation is believed to be the cause of progressing liver disease in patients with AAT deficiency.

Fazirsiran 是一種潛在的一流研究性 RNAi 療法，旨在減少稱為 Z-AAT 的突變形式 alpha-1 抗胰蛋白酶蛋白的產生，作為與 alpha-1 抗胰蛋白酶缺乏症相關的罕見遺傳性肝病 Z-AAT 的潛在治療方法AAT 積累被認為是 AAT 缺乏患者肝病進展的原因。

Reducing production of pro-inflammatory Z-AAT protein has the potential to halt the progression of liver disease and potentially allow the liver to regenerate and repair. The data from this program are exciting and encouraging. The open-label AROAAT-2002 Phase II study in 16 patients with AATD liver disease suggest a strong effect and the potential to improve multiple downstream markers of liver health.

減少促炎 Z-AAT 蛋白的產生有可能阻止肝病的進展，並有可能使肝臟再生和修復。該計劃的數據令人興奮和鼓舞。對 16 名 AATD 肝病患者進行的開放標籤 AROAAT-2002 II 期研究表明，該藥物具有強大的作用，並有可能改善肝臟健康的多個下游標誌物。

Decrease in fibrosis severity of at least one stage occurred in 7 of 12 patients, or 58%, receiving the 200 milligram dose, including 2 patients with cirrhosis. All patients had reductions in accumulated total mutant Z-AAT in the liver with a median reduction at week 24 or 48 of 83%. Reductions in liver Z-AAT concentrations were also associated with histologic improvements in inflammation. After treatment, all patients had a decreased histologic globule burden, with the mean score decreasing by 69% at week 24 or 48.

接受 200 毫克劑量治療的 12 名患者中有 7 名（佔 58%）出現至少一個階段的纖維化嚴重程度降低，其中包括 2 名肝硬化患者。所有患者肝臟中累積的總突變體 Z-AAT 都有減少，第 24 週或第 48 週時的中位數減少為 83%。肝臟 Z-AAT 濃度的降低也與炎症的組織學改善有關。治療後，所有患者的組織學球負荷均有所降低，平均評分在第 24 週或第 48 週時下降了 69%。

Biomarkers of liver injury were also reduced. At baseline, mean ALT concentrations were above the upper limit of normal range in all cohorts. After treatment, ALT concentrations decreased in all cohorts from week 16 through week 52. All 12 patients with ALT concentrations above the upper limit of the normal range at baseline had reductions to normal levels at week 52.

肝損傷的生物標誌物也減少了。在基線時，平均 ALT 濃度高於所有隊列的正常範圍上限。治療後，從第 16 周到第 52 週，所有隊列的 ALT 濃度均下降。所有 12 名基線時 ALT 濃度高於正常範圍上限的患者在第 52 週時均降至正常水平。

In addition to activity and efficacy measures, safety and tolerability measures continue to be encouraging. Fazirsiran was generally well tolerated in the 2002 study. Over a period of 1.5 years, there were no deaths, discontinuations of treatment with fazirsiran, or dose interruptions. The most common adverse events that emerged or worsened after the first administration of fazirsiran were arthralgia and transient increased concentrations of blood creatinine kinase. There were no apparent dose dependent increases in the frequency or severity of adverse events.

除了活性和功效措施外，安全性和耐受性措施繼續令人鼓舞。在 2002 年的研究中，Fazirsiran 的耐受性普遍良好。在 1.5 年的時間裡，沒有死亡、fazirsiran 治療中斷或劑量中斷。首次服用 fazirsiran 後出現或惡化的最常見不良事件是關節痛和血肌酐激酶濃度短暫升高。不良事件的頻率或嚴重程度沒有明顯的劑量依賴性增加。

So far, there have been no major pulmonary adverse events resulting in drug or trial discontinuations. 4 of the 6 patients who entered the trial while receiving AAT augmentation therapy had a history of emphysema, and none reported exacerbations.

到目前為止，還沒有發生導致藥物或試驗中斷的重大肺部不良事件。在接受 AAT 增強治療時進入試驗的 6 名患者中有 4 名有肺氣腫病史，沒有人報告加重。

Fazirsiran Phase II placebo-controlled SEQUOIA study has also reached the end of the treatment period. We collected the final 12-month biopsy from the final patient recently, and will now be processing samples and analyzing data over the coming months. The deadline is in September to submit a late-breaker to present at the AASLD Liver Meeting in November.

Fazirsiran II 期安慰劑對照的 SEQUOIA 研究也已經到了治療期的末尾。我們最近從最後一名患者身上收集了最後 12 個月的活檢，現在將在未來幾個月內處理樣本和分析數據。截止日期是 9 月，提交遲到者將在 11 月的 AASLD 肝臟會議上發表。

The timing will be tight to have enough data to justify a late-breaker, so it is a low probability that we will be presenting data at that congress. We should, however, have a rather complete dataset on SEQUOIA in the fourth quarter of this year, so we and our partners at Takeda will together determine the best way to communicate those results publicly.

時間緊迫，無法獲得足夠的數據來證明後來者的合理性，因此我們在那次大會上展示數據的可能性很小。然而，我們應該在今年第四季度擁有一個相當完整的 SEQUOIA 數據集，因此我們和我們在 Takeda 的合作夥伴將共同確定公開傳達這些結果的最佳方式。

Regarding status of a Phase III study, we and Takeda are in the process of having discussions with regulators on the development path. We do not want to comment specifically on those discussions as they are ongoing.

關於 III 期研究的狀態，我們和武田正在與監管機構就開發路徑進行討論。我們不想對這些討論進行具體評論，因為它們正在進行中。

Moving on to our cardiometabolic candidates. I will provide the status of the VISTA studies of ARO-ANG3 and the SUMMIT studies of ARO-APOC3. The VISTA program of ARO-ANG3, our investigational medicine designed to reduce production of angiopoietin-like protein 3 as a potential treatment for patients with dyslipidemia, has 2 ongoing studies.

繼續我們的心臟代謝候選人。我將提供 ARO-ANG3 的 VISTA 研究和 ARO-APOC3 的 SUMMIT 研究的狀態。 ARO-ANG3 的 VISTA 項目是我們的研究藥物，旨在減少血管生成素樣蛋白 3 的產生，作為血脂異常患者的潛在治療方法，目前正在進行 2 項研究。

The first, ARCHES-2 in 204 patients with mixed dyslipidemia, is fully enrolled. We anticipate that the ARCHES-2 will be complete around the end of 2022 and top line data will be available to share in the first half of 2023. In addition to the planned study period, patients will be eligible to continue in an open-label extension period after completing the week 36 visit.

第一個是 204 名混合性血脂異常患者的 ARCHES-2，已完全註冊。我們預計 ARCHES-2 將在 2022 年底左右完成，頂線數據將在 2023 年上半年共享。除了計劃的研究期外，患者將有資格繼續在開放標籤完成第 36 周訪問後的延長期。

The second active study of ARO-ANG3 is GATEWAY in up to 16 subjects with homozygous familial hypercholesterolemia, or HoFH. We anticipate that this study will be fully enrolled by the end of the year, and we intend to share data in 2023 when possible.

ARO-ANG3 的第二項活躍研究是在多達 16 名患有純合子家族性高膽固醇血症或 HoFH 的受試者中進行的 GATEWAY 研究。我們預計這項研究將在今年年底之前完成全部入組，我們打算在可能的情況下在 2023 年共享數據。

Moving on to ARO-APOC3. The SUMMIT program of ARO-APOC3, our investigational medicine targeting apolipoprotein C-III being studied in patients with various lipid disorders, has 3 ongoing studies. 2 Phase II studies; SHASTA-2 in patients with severe hypertriglyceridemia, or SHTG; and MUIR in patients with mixed dyslipidemia; and the Phase III PALISADE study in patients with familial chylomicronemia syndrome, or FCS.

轉到 ARO-APOC3。 ARO-APOC3 的 SUMMIT 計劃是我們針對載脂蛋白 C-III 的研究藥物，正在對患有各種脂質紊亂的患者進行研究，目前有 3 項正在進行的研究。 2 II 期研究；嚴重高甘油三酯血症或 SHTG 患者的 SHASTA-2；混合性血脂異常患者的 MUIR；以及針對家族性乳糜微粒血症綜合徵或 FCS 患者的 III 期 PALISADE 研究。

MUIR has now reached the total planned enrollment of 320 patients. We have a number of patients still in screening, so we will allow some additional patients to join the study but are not screening any new patients. SHASTA-2 has enrolled over 80% of the planned number of patients, and we anticipate full enrollment this year. This would allow for both studies to be completed in 2023.

MUIR 現在已經達到了 320 名患者的計劃入組總數。我們有一些患者仍在篩查中，因此我們將允許一些額外的患者加入研究，但不會篩查任何新患者。 SHASTA-2 已經招募了超過 80% 的計劃患者，我們預計今年將全面招募。這將使兩項研究都能在 2023 年完成。

PALISADE is planned to enroll approximately 72 patients with FCS. We continue to open new clinical sites around the world and enroll new patients into the study. We are still on schedule and anticipate that PALISADE will reach full enrollment in the middle of 2023, which would allow for study completion in 2024.

PALISADE 計劃招募大約 72 名 FCS 患者。我們繼續在世界各地開設新的臨床站點，並招募新患者參與研究。我們仍在按計劃進行，預計 PALISADE 將在 2023 年年中實現全面招生，這將使研究能夠在 2024 年完成。

I will now turn the call over to Dr. James Hamilton. James?

我現在將電話轉給 James Hamilton 博士。詹姆士？

(technical difficulty) some updates on some of our earlier stage development programs. Let's start with the pulmonary platform.

（技術難度）我們一些早期開發項目的一些更新。讓我們從肺部平台開始。

As Chris mentioned, we hosted an R&D Day on our emerging pipeline of pulmonary targeted RNAi therapeutics and the technology platform that these candidates are built upon. We have learned a great deal about the platform with details provided in the archived pulmonary R&D Day webcast available on our website.

正如 Chris 提到的，我們在我們新興的肺部靶向 RNAi 療法和這些候選人所建立的技術平台上舉辦了研發日。我們在我們網站上存檔的肺部研發日網絡廣播中提供了有關該平台的大量信息和詳細信息。

In summary, we believe that we now have improved siRNA triggers with longer pharmacodynamic duration allowing less frequent dose administration, which are less likely to overload lung clearance mechanisms and are less likely to induce pulmonary inflammation. This gives us increased confidence in the platform as we move forward with current and planned future clinical studies and additional toxicology studies. We also presented preclinical data on the development of our next-generation pulmonary candidates, ARO-MUC5AC and ARO-RAGE, which have recently begun dosing in clinical studies, and ARO-MMP7, which will be approaching clinical studies later this year.

總之，我們相信我們現在已經改進了 siRNA 觸發器，其藥效學持續時間更長，允許給藥頻率更低，這不太可能使肺清除機制超載，也不太可能誘發肺部炎症。隨著我們推進當前和計劃中的未來臨床研究和其他毒理學研究，這使我們對該平台更有信心。我們還提供了關於我們的下一代肺部候選藥物 ARO-MUC5AC 和 ARO-RAGE 的開發的臨床前數據，它們最近開始在臨床研究中給藥，以及 ARO-MMP7 將在今年晚些時候進行臨床研究。

ARO-MUC5AC is the first investigational medicine to directly silence expression of pathologic MUC5AC, a mucin protein with upregulated expression in the asthmatic airway, and potentially address muco-obstructive disease, characterized by mucus hypersecretion in a fundamentally different way than current therapies. Preclinical results have shown deep silencing of up to 70% to 90% of induced MUC5AC expression in mice and primates. In a sheep model of allergic asthma, ARO-MUC5AC effectively preserved airway function.

ARO-MUC5AC 是第一個直接沉默病理性 MUC5AC 表達的研究藥物，MUC5AC 是一種在哮喘氣道中表達上調的粘蛋白，並可能解決粘液阻塞性疾病，其特徵是粘液分泌過多，其特點與目前的療法截然不同。臨床前結果表明，在小鼠和靈長類動物中，高達 70% 至 90% 的誘導 MUC5AC 表達深度沉默。在過敏性哮喘的綿羊模型中，ARO-MUC5AC 有效地保護了氣道功能。

ARO-RAGE is an investigational medicine designed to reduce expression of the receptor for advanced glycation end products that aims to achieve broader anti-inflammatory effects compared to current biologics and with a more convenient inhaled mode of administration. Preclinical studies have shown that single inhaled doses of ARO-RAGE in rats and primates led to reductions of greater than 90% in lung RAGE mRNA and in serum sRAGE protein, a circulating biomarker for RAGE target engagement in the lung. Pharmacodynamic response appears to be highly durable enabling bimonthly or quarterly dosing.

ARO-RAGE 是一種研究藥物，旨在減少晚期糖基化終產物受體的表達，與目前的生物製劑相比，旨在實現更廣泛的抗炎作用，並採用更方便的吸入給藥方式。臨床前研究表明，在大鼠和靈長類動物中單次吸入劑量的 ARO-RAGE 可導致肺部 RAGE mRNA 和血清 sRAGE 蛋白減少超過 90%，血清 sRAGE 蛋白是肺部 RAGE 靶標參與的循環生物標誌物。藥效學反應似乎非常持久，可以每兩個月或每季度給藥一次。

Earlier this month, we announced that we had dosed the first subjects in Phase I/IIa clinical trials of both ARO-MUC5AC and ARO-RAGE. We have since completed dosing the first cohort of healthy volunteers in both studies. Both studies have 3 parts, consisting of single ascending and multiple ascending doses in normal healthy volunteers, and multiple dose cohorts in asthma patients with dose levels selected for patient cohorts based on data from normal healthy volunteers.

本月早些時候，我們宣布我們已經對 ARO-MUC5AC 和 ARO-RAGE 的 I/IIa 期臨床試驗的第一批受試者進行了給藥。我們已經完成了兩項研究中第一批健康志願者的給藥。這兩項研究分為 3 個部分，包括在正常健康志願者中的單次遞增劑量和多次遞增劑量，以及在哮喘患者中的多劑量隊列，根據來自正常健康志願者的數據為患者隊列選擇劑量水平。

The third pulmonary program we discussed at the R&D day is ARO-MMP7, our newest and previously undisclosed candidate designed to the reduce expression of matrix metalloproteinase 7, or MMP7, as a potential treatment for idiopathic pulmonary fibrosis, or IPF. MMP7 plays multiple roles in IPF pathogenesis, including promoting inflammation and aberrant epithelial repair and fibrosis. Silencing MMP7 expression in a rat IPF model reduced inflammatory cell infiltration, limited lung fibrosis, and preserved pulmonary function. We are conducting CTA-enabling work and preparation now, and we are on track to file this year to initiate first-in-human clinical studies.

我們在研發日討論的第三個肺部項目是 ARO-MMP7，這是我們之前未公開的最新候選藥物，旨在減少基質金屬蛋白酶 7 或 MMP7 的表達，作為特發性肺纖維化或 IPF 的潛在治療方法。 MMP7 在 IPF 發病機制中發揮多種作用，包括促進炎症和異常上皮修復和纖維化。在大鼠 IPF 模型中沉默 MMP7 表達可減少炎症細胞浸潤、限制肺纖維化和保留肺功能。我們現在正在進行 CTA 支持工作和準備工作，我們有望在今年提交申請以啟動首次人體臨床研究。

Our last early-stage clinical program is ARO-C3, our investigational RNAi therapeutic designed to reduce production of complement component 3, or C3, as a potential therapy for various complement mediated diseases. We are approaching the final healthy volunteer cohort in Part 1 of a Phase I/II study. Data from Part 1 will inform dose selection for Part 2, which will include eligible subjects with paroxysmal nocturnal hemoglobinuria, or PNH, and complement-mediated renal diseases, including IgA nephropathy and C3 glomerulopathy. We anticipate that Part 2 of the study will start before the end of the year.

我們最後一個早期臨床項目是 ARO-C3，這是我們的研究性 RNAi 療法，旨在減少補體成分 3 或 C3 的產生，作為各種補體介導疾病的潛在療法。我們正在接近 I/II 期研究第 1 部分中的最終健康志願者隊列。第 1 部分的數據將為第 2 部分的劑量選擇提供信息，其中包括患有陣發性睡眠性血紅蛋白尿症或 PNH 以及補體介導的腎病（包括 IgA 腎病和 C3 腎小球病）的符合條件的受試者。我們預計該研究的第 2 部分將在今年年底前開始。

I will now turn the call over to Ken Myszkowski. Ken?

我現在將把電話轉給 Ken Myszkowski。肯？

Thank you, James, and good afternoon, everyone.

謝謝你，詹姆斯，大家下午好。

As we reported today, our net loss for the 3 months ended June 30, 2022 was $72.0 million or $0.68 per share based on 105.8 million fully diluted weighted average shares outstanding. This compares with net loss of $29.9 million, or $0.29 per share based on 104.1 million fully diluted weighted average shares outstanding for the 3 months ended June 30, 2021.

正如我們今天報導的那樣，我們截至 2022 年 6 月 30 日的三個月的淨虧損為 7200 萬美元或每股 0.68 美元，基於 1.058 億股完全稀釋的加權平均流通股。相比之下，截至 2021 年 6 月 30 日止三個月，淨虧損為 2990 萬美元，或每股 0.29 美元，基於 1.041 億股完全稀釋的加權平均流通股。

Revenue for the quarter ended June 30, 2022 was $32.4 million, compared to $45.9 million for the quarter ended June 30, 2021. Revenue in the current period primarily relates to our collaboration agreements with Takeda and Horizon. Revenue will be recognized as we complete our performance obligations, which include managing the ongoing AAT Phase II clinical trials for Takeda, and delivering a Phase I ready candidate to Horizon.

截至 2022 年 6 月 30 日的季度收入為 3240 萬美元，而截至 2021 年 6 月 30 日的季度收入為 4590 萬美元。當期收入主要與我們與武田和 Horizon 的合作協議有關。收入將在我們完成履行義務時確認，其中包括管理武田正在進行的 AAT II 期臨床試驗，並向 Horizon 提供 I 期準備好的候選藥物。

There remains $142.1 million of revenue to be recognized associated with the Takeda collaboration, which we anticipate will be recognized over approximately 2 years. And there remains $13 million of revenue to be recognized for Horizon, which we anticipate will be recognized by the end of calendar 2022. Revenue in the prior period primarily related to the recognition of a portion of the milestones received from our license and collaboration agreements with Janssen and Takeda.

與武田合作相關的收入仍有 1.421 億美元待確認，我們預計這將在大約 2 年內確認。 Horizon 仍有 1300 萬美元的收入需要確認，我們預計這將在 2022 日曆年底確認。上一期間的收入主要與確認從我們的許可和合作協議中收到的部分里程碑有關詹森和武田。

Total operating expenses for the quarter ended June 30, 2022 were $105.3 million, compared to $77.8 million for the quarter ended June 30, 2021. This increase is driven by higher employee compensation expense, including stock compensation expense, as well as higher R&D discovery expense.

截至 2022 年 6 月 30 日的季度總運營費用為 1.053 億美元，而截至 2021 年 6 月 30 日的季度為 7780 萬美元。這一增長是由於員工薪酬支出增加（包括股票補償支出）以及研發發現支出增加所致.

Net cash used by operating activities during the quarter ended June 30, 2022 was $68.9 million, compared with net cash used by operating activities of $29.6 million for the quarter ended June 30, 2021. The increase in cash used by operating activities is driven by higher expenses in research and development and we expect our operating cash burn to be USD70 million to USD80 million next quarter. And I will provide additional guidance during our year end conference call.

截至 2022 年 6 月 30 日的季度，經營活動使用的現金淨額為 6890 萬美元，而截至 2021 年 6 月 30 日的季度，經營活動使用的現金淨額為 2960 萬美元。經營活動使用的現金增加是由於較高的研發費用，我們預計下個季度我們的運營現金消耗將達到 7000 萬美元至 8000 萬美元。我將在年終電話會議期間提供更多指導。

Turning to our balance sheet. Our cash and investments totaled $582.4 million at June 30, 2022, compared to $613.4 million at September 30, 2021. The decrease in our cash and investments was primarily due to cash used for operating activities, mostly offset by cash inflows from GSK and the cash investment in our joint venture, Visirna. Our common shares outstanding at June 30, 2022, were 105.8 million.

轉向我們的資產負債表。截至 2022 年 6 月 30 日，我們的現金和投資總額為 5.824 億美元，而 2021 年 9 月 30 日為 6.134 億美元。我們的現金和投資減少主要是由於用於經營活動的現金，大部分被 GSK 的現金流入和現金抵消投資我們的合資企業 Visirna。截至 2022 年 6 月 30 日，我們的已發行普通股為 1.058 億股。

With that brief overview, I will now turn the call back to Chris.

有了這個簡短的概述，我現在將把電話轉回給克里斯。

Thanks, Ken.

謝謝，肯。

We have a large and growing pipeline of clinical drug candidates, providing us with the opportunity to help millions of patients and create a substantial amount of value. It also affords us the opportunity to regularly report clinical data so stakeholders can follow our progress. However, with the development of next-generation pulmonary candidates and timing of other studies, we have been in a bit of a data desert over the last several quarters.

我們擁有龐大且不斷增長的臨床候選藥物管道，為我們提供了幫助數百萬患者並創造大量價值的機會。它還使我們有機會定期報告臨床數據，以便利益相關者可以關注我們的進展。然而，隨著下一代肺候選藥物的開發和其他研究的時間安排，我們在過去幾個季度一直處於數據荒漠中。

We are now emerging from that desert. Between now and the end of next year, I expect at least 12 clinical readouts between our wholly-owned and partnered programs. They include the following. One, biopsy data from the SEQUOIA study in AAT with fazirsiran. 2, Phase I/II data from ARO-C3 in healthy volunteers and different patient populations.

我們現在正在走出那片沙漠。從現在到明年年底，我預計我們的全資項目和合作項目之間至少會進行 12 次臨床試驗。它們包括以下內容。一，來自 SEQUOIA 在 AAT 中使用 fazirsiran 的研究的活檢數據。圖 2，來自健康志願者和不同患者群體的 ARO-C3 的 I/II 期數據。

3, Phase I/II data from ARO-RAGE in healthy volunteers and patients. 4, Phase I/II data from ARO-MUC5AC in healthy volunteers and patients. 5, Phase II data from olpasiran in Amgen's Lp(a) study. Sixth, Phase II data from the ARO-ANG3 Arches-2 study in mixed dyslipidemia. 7, Phase II data from the ARO-ANG3 GATEWAY study in HoFH.

3，ARO-RAGE 在健康志願者和患者中的 I/II 期數據。 4，ARO-MUC5AC 在健康志願者和患者中的 I/II 期數據。 5，Amgen 的 Lp(a) 研究中來自 olpasiran 的 II 期數據。第六，來自混合性血脂異常的 ARO-ANG3 Arches-2 研究的 II 期數據。圖 7，來自 HoFH 的 ARO-ANG3 GATEWAY 研究的 II 期數據。

8, Phase II data from the ARO-APOC3 Muir study in mixed dyslipidemia. 9, Phase II data from the ARO-APOC3 SHASTA-2 study in severe hypertriglyceridemia. 10, Phase I data from ARO-MMP7 in healthy volunteers and possibly IPF patients. 11, Phase II data from various Janssen studies of JNJ-3989 in HBV patients, and 12, Phase I data from Janssen's NASH study with JNJ-0795.

圖 8，來自混合性血脂異常的 ARO-APOC3 Muir 研究的 II 期數據。圖 9，來自嚴重高甘油三酯血症的 ARO-APOC3 SHASTA-2 研究的 II 期數據。圖 10，來自健康志願者和可能的 IPF 患者的 ARO-MMP7 的 I 期數據。圖 11，來自 Janssen 對 HBV 患者進行的 JNJ-3989 多項研究的 II 期數據，以及 12，來自 Janssen 使用 JNJ-0795 進行的 NASH 研究的 I 期數據。

We are excited about these and other programs and look forward to updating you on our progress. Thank you for joining us today. And I would now like to open the call to your questions.

我們對這些和其他計劃感到興奮，並期待向您通報我們的最新進展。感謝您今天加入我們。我現在想開始回答你的問題。

Operator?

操作員？

(Operator Instructions) Our first question comes from Luca Issi with RBC.

（操作員說明）我們的第一個問題來自 RBC 的 Luca Issi。

Great. I have 2 quick ones. Maybe one, Javier. Congrats on publishing, obviously, the New England Journal Medicine. I think the 100-milligram dose and the 200-milligram dose have essentially [hyperimposable] PD curves in the serum. However, the improvement in fibrosis only occurred in high dose and not in the low dose. So just wondering what's the best way to rationalize that difference? And then maybe quickly on the cash position. You're obviously still fairly well capitalized, however, your OpEx and CapEx are both going up. So wondering how you're thinking about options to extend your runway?

偉大的。我有2個快速的。也許一個，哈維爾。顯然，祝賀《新英格蘭醫學雜誌》的出版。我認為 100 毫克劑量和 200 毫克劑量在血清中基本上具有 [hyperimposable] PD 曲線。然而，纖維化的改善只發生在高劑量而不是低劑量。所以只是想知道合理化這種差異的最佳方法是什麼？然後可能很快就會出現現金頭寸。您顯然仍然資本充足，但是，您的 OpEx 和 CapEx 都在上升。所以想知道您如何考慮延長跑道的選擇？

This is Javier. So if you think about the 2002 study, we enrolled 12 patients in the 200-milligram dose. All of them had a biopsy of 6 months and 8 of them at 12 months. And we only enrolled 4 patients in the 100-milligram dose, and they all have a pair biopsy in between 6 months. With a caveat that one of the 4 patients in the 100-milligram did not have the paired biopsies, so we can't report in those patients. So, we only have 3 patients in the 100-milligrams that has very robust effect on Z protein, ALTs, liver Z protein, globule and inflammation, but we didn't see a change in fibrosis at that early point in those 3 patients. So, I think it's a little bit about the small numbers.

這是哈維爾。所以如果你想想 2002 年的研究，我們招募了 12 名服用 200 毫克劑量的患者。他們都在 6 個月時進行了活檢，其中 8 人在 12 個月時進行了活檢。而我們在 100 毫克劑量中只招募了 4 名患者，他們都在 6 個月之間進行了一對活檢。需要注意的是，100 毫克的 4 名患者中有一名沒有進行配對活檢，因此我們無法報告這些患者。因此，我們只有 3 名患者在 100 毫克中對 Z 蛋白、ALT、肝臟 Z 蛋白、小球和炎症有非常強大的影響，但我們在這 3 名患者的早期沒有看到纖維化的變化。所以，我認為這與小數字有關。

In contrast, as you said, in the 12 patients that received 200 milligrams, we saw all the improvement in the different biomarkers and parameters. We also saw 7 out of 12 improvement in fibrosis. I think the reason here is likely to be the small sample size, the variability of leading fibrosis, which is well known. And you're right that the magnitude of the PD effect is very consistent between the 100 and 200 milligrams. But we believe that when you put all the data together, absence of any safety issue between 100 and 200 milligrams, very consistent suppression of the Z protein. When you look at the PK and the PD, there are small differences, but I think it favored the 200-milligram dose. So, I think when you put all the information together, there are reasons to see the 200 milligrams as the best dose to move forward. And as I said, the difference in fibrosis is likely to be variability in a small sample size.

相比之下，正如您所說，在接受 200 毫克劑量的 12 名患者中，我們看到了不同生物標誌物和參數的所有改善。我們還看到 12 個中有 7 個在纖維化方面有所改善。我認為這裡的原因可能是樣本量小，導致纖維化的可變性，這是眾所周知的。你是對的，局部放電效應的大小在 100 和 200 毫克之間非常一致。但我們相信，當您將所有數據放在一起時，100 到 200 毫克之間不存在任何安全問題，對 Z 蛋白的抑制非常一致。當您查看 PK 和 PD 時，差異很小，但我認為它有利於 200 毫克劑量。所以，我認為當您將所有信息放在一起時，有理由將 200 毫克視為前進的最佳劑量。正如我所說，纖維化的差異可能是小樣本量的變異性。

And Luca, I'll take the cash question. So I agree, I feel comfortable with our cash position right now in large part because we have right now 6 partnerships with 5 different companies, if I have my math right. And those partnerships are maturing. I think that we have access to a substantial amount of capital across all those partnerships over the next 12 months to 24 months. So, we feel good about that inflow. But also, as you know, Luca, we're really good at pushing new drug candidates in the clinic. We've got a pipeline -- a clinical pipeline right now of 10 or 11 candidates, and I think that grows to 20 in the next few years. And I think that's important ammunition to do the future deals.

盧卡，我來回答現金問題。所以我同意，我現在對我們的現金狀況感到滿意，這在很大程度上是因為如果我沒記錯的話，我們現在與 5 家不同的公司建立了 6 個合作夥伴關係。這些夥伴關係正在走向成熟。我認為在接下來的 12 個月到 24 個月內，我們可以通過所有這些合作夥伴關係獲得大量資金。因此，我們對這種流入感到滿意。但是，正如你所知，盧卡，我們真的很擅長在臨床上推動新的候選藥物。我們有一條管道——目前有 10 或 11 名候選人的臨床管道，我認為在未來幾年內會增加到 20 人。我認為這是進行未來交易的重要彈藥。

Now, I think we'll be pretty choosy about that. And I think that ultimately, the majority of our pipeline will be wholly owned and will commercialize ourselves, but we will have access to other non-core assets that we can partner. I would expect, on average, of around a deal a year, a new deal a year to be about the right cadence. That may change from year-to-year. But I think, on average, that's probably the way to think about it. And I just think that gives us access to as much capital as we need in the near term.

現在，我認為我們會非常挑剔。我認為最終，我們的大部分管道將是全資擁有的，並將自己商業化，但我們將能夠獲得我們可以合作的其他非核心資產。我預計，平均而言，每年大約有一項交易，每年有一項新交易是正確的節奏。這可能會逐年變化。但我認為，平均而言，這可能是思考它的方式。我只是認為這使我們能夠在短期內獲得我們需要的盡可能多的資金。

Our next question comes from Maury Raycroft with Jefferies.

我們的下一個問題來自 Jefferies 的 Maury Raycroft。

This is Farzin on for Maury. Can you say some expectations for the Phase II AAT SEQUOIA data and the [effect sizes] you'd expect to achieve?

這是莫里的 Farzin。你能說說你對 AAT SEQUOIA II 期數據的一些期望和你期望達到的[效果大小]嗎？

Yes. I don't think we are going to want to get in to front running that. We haven't seen those data yet. Look, we feel -- we are looking forward to seeing those data. The data so far that we've seen have been consistent, as Javier said, we've seen circulating AAT levels and it's consistent across patients. We've seen in a handful of patients in the open-label study with a good histological response in 6 months to 12 months. And so we expect -- we're looking forward to seeing those data. I don't want to put any expectations around them, but I wouldn't expect the basic story to change. And I just think my hope is that the SEQUOIA data just reinforced the existing story.

是的。我不認為我們會想搶先一步。我們還沒有看到這些數據。看，我們覺得——我們期待看到這些數據。到目前為止，我們看到的數據是一致的，正如 Javier 所說，我們看到了循環 AAT 水平，並且在患者之間是一致的。我們在開放標籤研究中看到少數患者在 6 個月到 12 個月內具有良好的組織學反應。所以我們期待——我們期待看到這些數據。我不想對他們抱有任何期望，但我不希望基本故事發生變化。我只是認為我希望 SEQUOIA 數據只是加強了現有的故事。

Our next question comes from Ted Tenthoff with Piper Sandler.

我們的下一個問題來自 Ted Tenthoff 和 Piper Sandler。

So, I guess picking up a little bit on the last question and again, appreciating that there's -- we'll see what the data has to say. Walk us through sort of how you guys are seeing the potential paths forward? How you and Takeda are sort of discussing it following the data for ATT -- AAT?

所以，我想再次回答最後一個問題，感謝有——我們將看看數據要說什麼。帶我們了解一下你們如何看待潛在的前進道路？你和武田是如何根據 ATT -- AAT 的數據進行討論的？

Look, I'm a middle child, and I like to give people what they want, but I can't give you that. We are in -- or Takeda is in discussions with the FDA, and we're just going to have to wait to see where those go. We feel comfortable that the FDA -- we are aligned with the FDA in appreciating the importance of this disease and the fact that there's no good treatment for it right now, liver disease associated with AAT. We've got, I think, the only thing in the clinic that really offers these patients hope. And so my hope is that we can get to alignment reasonably soon with the regulators. But I can't really give you an idea about where that's going. Now the SEQUOIA data, I think will be -- could be helpful because it just gives us more numbers. And hopefully, we see what we've been seeing in the smaller open-label study. But that should -- my hope is that, that will help the discussions along, but we'll see how that goes.

看，我是個中二孩子，我喜歡給人們他們想要的東西，但我不能給你。我們正在——或者武田正在與 FDA 進行討論，我們只需要拭目以待。我們對 FDA 感到滿意——我們與 FDA 一致認識到這種疾病的重要性，以及目前還沒有很好的治療方法的事實，即與 AAT 相關的肝病。我認為，我們擁有診所中唯一真正為這些患者帶來希望的東西。因此，我希望我們能夠盡快與監管機構保持一致。但我真的不能告訴你這是怎麼回事。現在，我認為 SEQUOIA 數據會很有幫助，因為它給了我們更多的數字。希望我們能看到我們在較小的開放標籤研究中看到的結果。但這應該——我希望這將有助於討論的進行，但我們將看看進展如何。

Our next question comes from Ellie Merle with UBS.

我們的下一個問題來自瑞銀的 Ellie Merle。

Just on the pulmonary franchise, if I heard exactly, you've completed dosing in the first cohort in healthy volunteers for MUC5AC and RAGE. I guess, I know that we're starting with sort of single ascending dose here in healthy volunteers. But I guess, what are sort of the circulating biomarkers or measures of these protein levels taken in these healthy volunteers and any kind of initial data points in terms of target engagement here?

就肺部專營權而言，如果我聽到的準確的話，您已經在第一批健康志願者中完成了 MUC5AC 和 RAGE 的給藥。我想，我知道我們從健康志願者的單次遞增劑量開始。但我想，這些健康志願者的循環生物標誌物或這些蛋白質水平的測量方法是什麼，以及在目標參與方面的任何類型的初始數據點？

And then, I guess, as you move into the multiple ascending dose as well as -- into patient dosing, I mean even, I guess, early on and even just healthy in that dosing, could we potentially get some of these biomarkers as well just in terms of target engagement? And I guess, first, if you're measuring it, but then also thinking about from our perspective where we set the time frame under what we could potentially learn about this?

然後，我想，當你進入多次遞增劑量以及 - 進入患者劑量時，我的意思是，我想，即使在早期甚至只是健康的劑量下，我們也可能獲得這些生物標誌物中的一些就目標參與而言？我想，首先，如果你正在衡量它，然後從我們的角度考慮我們將時間框架設定在我們可能了解的情況下？

So James, why don't you talk about what we're measuring and then I'll address the question about information flow.

那麼 James，你為什麼不談談我們正在測量的內容，然後我將解決有關信息流的問題。

Sure. Yes. So both -- you're right, we completed the first cohort for both ARO-MUC5AC and ARO-RAGE. It's an ascending -- single ascending dose study. We start with the lowest dose, of course. And we measure in the multi C study, we measure sputum MUC5AC levels. And then we will also, in that study, measure expression of MUC5AC in Bronchoalveolar lavage fluid. So, there's not a blood biomarker for MUC5AC, but it's sputum and BAL based. And those have been drawn, but we haven't -- there's a lag. We haven't seen any of that yet. And similarly, for RAGE, there is a blood biomarker sRAGE, which is -- and drawn -- that will be drawn on all the healthy volunteer cohorts as well as in the patient cohorts. We will also look at sputum RAGE levels and RAGE in the bulk fluid as well. So, there's several different biomarkers that we can look at in both studies.

當然。是的。所以兩者——你是對的，我們完成了 ARO-MUC5AC 和 ARO-RAGE 的第一個隊列。這是一項遞增的單次遞增劑量研究。當然，我們從最低劑量開始。我們在多 C 研究中測量，我們測量痰液 MUC5AC 水平。然後，在該研究中，我們還將測量支氣管肺泡灌洗液中 MUC5AC 的表達。因此，沒有 MUC5AC 的血液生物標誌物，但它是基於痰液和 BAL 的。那些已經畫好了，但我們還沒有——有一個滯後。我們還沒有看到這些。類似地，對於 RAGE，有一個血液生物標誌物 sRAGE，它是——並且是抽取的——將在所有健康的志願者隊列和患者隊列中抽取。我們還將查看痰液中的 RAGE 水平和大量液體中的 RAGE。因此，我們可以在這兩項研究中查看幾種不同的生物標誌物。

And regarding data flow, so my expectation is that certainly in '23, we'll have results from those studies. If we, to be more granular, are there opportunities for us to release data earlier than when the entire studies are completed? That's a possibility, but we just don't have any visibility on that right now because the -- it is still ongoing and they're still fairly early in the studies. And so that's the best guidance I can give you, but I do expect whole data in '23, and I just don't know about partial data upstream of that.

關於數據流，所以我的期望是，在 23 年，我們肯定會從這些研究中得到結果。如果我們更詳細地說，我們是否有機會在整個研究完成之前發布數據？這是一種可能性，但我們現在對此沒有任何了解，因為它仍在進行中，而且他們還處於研究的早期階段。所以這是我能給你的最好指導，但我確實希望在 23 年獲得完整數據，我只是不知道上游的部分數據。

Got it. But I guess in terms of, internally, for you guys, even if these are healthy patients or healthy volunteers, you at least will, from these markers maybe get a bit of a sense in terms of whether or not you're engaging the target, perhaps even in the near term.

知道了。但我想就內部而言，對於你們來說，即使這些是健康的患者或健康的志願者，你至少會從這些標記中了解你是否正在參與目標，甚至可能在短期內。

Yes. I think that's fair. I think the data from healthy volunteers will teach us a lot. As James said, we have taken -- we have samples. We haven't seen anything yet. So, we have no data at this point. And of course, these are very low doses, I believe. So, I don't even know if we would see any knockdown of these early doses, but your point is a good one. I think that we can learn something from the healthy volunteers.

是的。我認為這很公平。我認為來自健康志願者的數據會教給我們很多東西。正如詹姆斯所說，我們已經採取了 - 我們有樣本。我們還沒有看到任何東西。所以，我們目前沒有數據。當然，我相信這些都是非常低的劑量。所以，我什至不知道我們是否會看到這些早期劑量的任何擊倒，但你的觀點是好的。我認為我們可以從健康的志願者身上學到一些東西。

Our next question comes from Joel Beatty with Baird.

我們的下一個問題來自 Joel Beatty 和 Baird。

What's the outlook currently for your platform for oncology programs?

您的腫瘤學項目平台目前前景如何？

Yes. So, I think we learned a lot this year and last year with the ARO-HIF2. As we've said in the past, I think the HIF2 market has changed a bit, and so it didn't make sense for us to push that candidate forward. I also think that we learned a lot about knockdown in oncology. The good news was, I think, we saw it. And I think we can do better. And so it's -- we are looking to continue to develop that platform. We have nothing in the near term. Don't expect anything this year in oncology. But we'll see where that goes going forward. It's not a real core of ours, but we do think there is value there, and we do think that RNAi may play a role in oncology at some point. And so we're still working on it.

是的。所以，我認為我們今年和去年通過 ARO-HIF2 學到了很多東西。正如我們過去所說，我認為 HIF2 市場發生了一些變化，因此我們推動該候選人前進沒有意義。我還認為我們在腫瘤學中學到了很多關於擊倒的知識。好消息是，我想，我們看到了。我認為我們可以做得更好。因此，我們希望繼續開發該平台。短期內我們什麼都沒有。今年不要對腫瘤學抱有任何期望。但我們會看到它的發展方向。它不是我們真正的核心，但我們確實認為那裡有價值，我們確實認為 RNAi 可能在某個時候在腫瘤學中發揮作用。所以我們仍在努力。

Our next question comes from Madhu Kumar with Goldman Sachs.

我們的下一個問題來自高盛的 Madhu Kumar。

So, one on AAT and one on the pulmonary program. So on AAT, I guess kind of the question we get a lot from people is, what do you think is the effective placebo rate of fibrosis improvement? And to what extent, do you think you can use the fraction of patients who had a worsening of fibrosis in the Phase II open-label extension study as an effective proxy for kind of sampling variability style placebo effects on kind of liver fibrosis improvement and worsening?

因此，一個關於 AAT，一個關於肺部計劃。所以在 AAT 上，我想我們從人們那裡得到的很多問題是，你認為安慰劑改善纖維化的有效率是多少？在何種程度上，您認為您可以使用 II 期開放標籤擴展研究中纖維化惡化的患者比例作為抽樣變異性類型安慰劑對肝纖維化改善和惡化的影響的有效代理？

And then on the pulmonary programs, you mentioned the idea of biomarker changes in healthy volunteers and in patients. I guess one question we get from people is, when do you expect to see kind of assessments of clinical benefit in the MUC5AC and RAGE programs as kind of clinical proof-of-concept metrics for those pulmonary RNAi programs?

然後在肺部計劃中，你提到了健康志願者和患者的生物標誌物變化的想法。我想我們從人們那裡得到的一個問題是，您預計什麼時候會看到 MUC5AC 和 RAGE 項目的臨床益處評估作為這些肺部 RNAi 項目的一種臨床概念驗證指標？

Javier, you want to address AAT?

哈維爾，你想解決 AAT？

Sure. Yes. So as you know, liver biopsies, the histology is very viable, particularly the fibrosis core systems and you normally require 2 pathologies within the biopsies and then (inaudible), which is what we did in both 2002 and SEQUOIA study. So it is -- so based on this -- the increasing variability and the data from some natural history studies is about 20% of people may have a regression without any treatment and about 20% could have or 30% can have progression in about 2 to 3 years' time. That's what at least one relatively small study show. When you look at NASH, the numbers are kind of similar. You see a 20% decrease without -- that's why sometimes it's difficult to power those studies.

當然。是的。所以正如你所知，肝臟活檢，組織學是非常可行的，特別是纖維化核心系統，你通常需要在活檢中進行 2 次病理檢查，然後（聽不清），這是我們在 2002 年和 SEQUOIA 研究中所做的。所以它是——所以基於此——不斷增加的變異性和來自一些自然歷史研究的數據是大約 20% 的人可能在沒有任何治療的情況下出現消退，大約 20% 的人可能有或 30% 的人可能在大約 2 年內出現進展到 3 年的時間。至少一項相對較小的研究表明了這一點。當您查看 NASH 時，數字有點相似。你會看到 20% 的減少沒有——這就是為什麼有時很難為這些研究提供動力。

And I think the second part of your question has to do with how many people have an increased score in the 2002 study. And 2 of the 15 patients have an increase of 1 point. Both of them have a very significant reduction in Z protein in the liver, globule burden. Actually, both of them went to 0, one of which started with 9, which is the highest score. So the (inaudible) exactly what was designed to do across the board. Those patients decrease in [installation] and yet they have a 1 point progression in February. So, I think that speaks to a reality fact, which is liver biopsy is challenging and the consequence of that, but you need to do the appropriate study with the appropriate methodology versus histology, and that's what we're doing.

我認為你問題的第二部分與有多少人在 2002 年的研究中得分增加有關。 15 名患者中有 2 名增加了 1 分。它們都非常顯著地減少了肝臟中的 Z 蛋白，小球負擔。其實兩個都是0，其中一個是9開頭的，也就是最高分。因此，（聽不清）正是為全面設計而設計的。這些患者的 [安裝] 減少，但他們在 2 月份有 1 點進展。所以，我認為這說明了一個現實事實，即肝活檢具有挑戰性及其後果，但您需要使用適當的方法與組織學進行適當的研究，這就是我們正在做的。

And then on the pulmonary front, I think for MUC5AC, if you look at the levels of MUC5AC expression in patients in the asthmatic versus expression in healthy volunteer, you probably need significant knockdown. So to start to see a change in phenotype based on MUC5AC knockdown, you're probably looking at 70% plus knockdown. And there is not the similar correlate for RAGE based on our animal data in the 2 different rodent models. Again, you need to achieve significant knockdown, a good magnitude of knockdown. So probably better than 70% to 75% knockdown, but I think the more is better for both of those.

然後在肺方面，我認為對於 MUC5AC，如果你比較哮喘患者和健康志願者的 MUC5AC 表達水平，你可能需要顯著降低。因此，要開始看到基於 MUC5AC 擊倒的表型變化，您可能正在查看 70% 以上的擊倒。根據我們在兩種不同囓齒動物模型中的動物數據，RAGE 沒有類似的相關性。同樣，您需要實現顯著的擊倒，一個很好的擊倒幅度。所以可能比 70% 到 75% 的擊倒要好，但我認為對兩者來說越多越好。

Well, my question is more on timing. Like when can we expect data to testing like force vital capacity and things and the [ASCO] trials and the kind of mucociliary disease trials?

好吧，我的問題更多是關於時機。就像我們什麼時候可以期待數據來測試力量肺活量和事物以及 [ASCO] 試驗和粘膜纖毛疾病試驗的類型？

Of course, we'll look at that in our current study, but that's not the focus of the current study. These are really more focused on biomarkers. So, no, I don't know we've talked timing on functional readouts like that.

當然，我們會在當前的研究中對此進行研究，但這不是當前研究的重點。這些實際上更側重於生物標誌物。所以，不，我不知道我們已經討論過像這樣的功能讀數的時間安排。

Yes. We have not. My expectation is to really look at those functional changes. You have to align on the Phase II studies. And so I don't think you'll -- as James said, we'll be looking for those things, but my expectation is that we don't really see those until Phase II.

是的。我們還沒有。我的期望是真正了解這些功能變化。你必須在 II 期研究上保持一致。所以我認為你不會 - 正如詹姆斯所說，我們會尋找這些東西，但我的期望是我們在第二階段之前不會真正看到這些東西。

Our next question comes from Patrick Trucchio with H.C. Wainwright.

我們的下一個問題來自 H.C. 的 Patrick Trucchio。溫賴特。

And congrats all the progress. I have a couple of follow-up questions. So first is on ARCHES-2. The top line data is expected in the first half of next year. I'm wondering if you can discuss what you'd be looking for in this data and discuss the anticipated differentiation from ANG3 from vupanorsen and why we should not expect ANG3 to have a similar outcome that came from that Phase IIb TRANSLATE trial?

並祝賀所有的進步。我有幾個後續問題。首先是 ARCHES-2。一線數據預計明年上半年。我想知道您是否可以討論您在這些數據中尋找的內容，並討論 ANG3 與 vupanorsen 的預期差異，以及為什麼我們不應該期望 ANG3 具有與 IIb 期 TRANSLATE 試驗相似的結果？

So the first part of the question, yes, we are expecting to have the data in the first half of next year. That means that we are hard to work on the next step at the end of Phase II. So, this will enable a Phase III study. So, I think I want to emphasize the relevance of this data in the first half of next year. So the comparison, I don't think is possible. 2 different drugs, 2 different technologies. We haven't seen in our Phase I study any of this. I mean it's not very clear yet reported from them. So at this point, we have no concern with regards to seeing any unexpected safety finding. We'll know that very soon.

所以問題的第一部分，是的，我們預計明年上半年會有數據。這意味著我們很難在第二階段結束時進行下一步工作。因此，這將使 III 期研究成為可能。所以，我想我想在明年上半年強調這個數據的相關性。所以比較，我認為是不可能的。 2種不同的藥物，2種不同的技術。在我們的第一階段研究中，我們還沒有看到任何這些。我的意思是他們的報告還不是很清楚。所以在這一點上，我們不擔心看到任何意外的安全發現。我們很快就會知道。

Got it. And then just with the GATEWAY program with HoFH, the study is fully enrolled with the data to follow in 2023. I'm wondering if you can discuss the anticipated path to approval in HoFH, and what you would need to demonstrate in this GATEWAY program from a safety and efficacy perspective? And is there a potential for an accelerated review? And finally, what would the potential commercialization look like in this patient population? Would you look to launch this on your own or with a partner? And just lastly, I guess, how large of an indication could this ultimately be?

知道了。然後，僅通過 HoFH 的 GATEWAY 計劃，該研究就完全納入了 2023 年的數據。我想知道您是否可以討論 HoFH 的預期批准途徑，以及您需要在此 GATEWAY 計劃中證明什麼從安全性和有效性的角度？是否有可能進行加速審查？最後，在這個患者群體中潛在的商業化會是什麼樣子？您希望自己推出還是與合作夥伴一起推出？最後，我想，這最終會有多大的跡象？

Well -- so HoFH is a rare condition. There is a drug approved with a similar pathway or the same pathway with an antibody. We're doing our first study, proof of concept. Of course, that will be our point of reference, how we compare with the antibody to ANGPTL3. We know that we do have an advantage there because the dosing will be every 3 months or 6 months, who knows, subcutaneously. So, we do have an advantage there. So, we need to see, and we will compare that data with them and say, are we competitive to the antibody in terms of efficacy, safety and tolerability, dose ranging and so forth.

嗯——所以 HoFH 是一種罕見的疾病。有一種藥物被批准具有相似的途徑或與抗體相同的途徑。我們正在進行我們的第一項研究，概念驗證。當然，這將是我們的參考點，我們如何與 ANGPTL3 抗體進行比較。我們知道我們在這方面確實有優勢，因為每 3 個月或 6 個月給藥一次，誰知道呢，皮下注射。所以，我們在那裡確實有優勢。所以，我們需要看看，我們將把這些數據與他們進行比較，然後說，我們在功效、安全性和耐受性、劑量範圍等方面是否與抗體有競爭力。

So we'll see. We're going to look at that data. As you know, the marker is terribly small. It will be competition against the antibody. And I think we feel that we have a very good profile to compete against them. We're going to move forward. The development process or program for this indication is well established. So it would be a relatively small study, placebo controlled. And we, like I said, the profile is as good as we expected, competitive to the Regeneron antibody. Then we are going to move forward because we think that there is a very unmet medical need, and this can offer a more friendly approach to this treatment.

所以我們拭目以待。我們將查看該數據。如您所知，標記非常小。它將與抗體競爭。而且我認為我們覺得我們有很好的形象可以與他們競爭。我們要向前邁進。該適應症的開發過程或程序已經確立。所以這將是一個相對較小的研究，安慰劑對照。就像我說的那樣，我們的形象和我們預期的一樣好，與再生元抗體具有競爭力。然後我們將繼續前進，因為我們認為有一個非常未滿足的醫療需求，這可以為這種治療提供更友好的方法。

And also, I want to say that the GATEWAY is not fully enrolled. So, we said we were enrolling efficiently, but it is not yet fully enrolled.

而且，我想說 GATEWAY 還沒有完全註冊。所以，我們說我們正在有效地註冊，但它還沒有完全註冊。

By the end of the year.

到今年年底。

Our next question comes from Keay Nakae with Chardan.

我們的下一個問題來自 Keay Nakae 和 Chardan。

A question about PALISADE. Last quarter, you talked about some trouble with some of the planned sites in Eastern Europe. Just wondering now what the outlook is in terms of how you're set up to enroll these patients? Again, how difficult are they to find?

關於 PALISADE 的問題。上個季度，您談到了一些東歐計劃站點的問題。現在只是想知道您如何設置招募這些患者的前景如何？再一次，他們有多難找到？

So we -- the only reason that we -- we didn't have any trouble in Europe other than this is a Phase III study with no Phase II study. So regulatory agencies and some ERBs raised that concern. They were, how do you know that there may be gaps in data to move from where you are to a Phase III study. And we addressed all those comments and questions, and I think we're in a very good shape now, getting many countries around the world approved to run this study. And it's important to recognize, and we said that to regulatory agencies that by the time that the Phase III study, the PALISADE study will be done, we're going to have 2 relatively large Phase II studies that will be part of that regulatory process.

所以我們 - 我們 - 我們在歐洲沒有遇到任何麻煩的唯一原因是這是一項沒有 II 期研究的 III 期研究。因此，監管機構和一些 ERB 提出了這種擔憂。他們是，你怎麼知道從你所在的地方轉移到 III 期研究的數據可能存在差距。我們解決了所有這些評論和問題，我認為我們現在的狀態非常好，讓世界上許多國家獲准開展這項研究。重要的是要認識到，我們對監管機構說，到 III 期研究、PALISADE 研究完成時，我們將進行 2 項相對較大的 II 期研究，這將成為監管過程的一部分.

So, I think the good news is, yes, we got some pushback from regulatory agencies and all of them so far accepted and understood the plan and the study is getting approved around the world, including Japan, where we had several meetings with them and the study is now approved in final negotiation with the sites and ready to start enrollment in Japan within a month or so. So not any unexpected delay other than more regulatory work to justify that we weren't ready for the Phase III study.

所以，我認為好消息是，是的，我們受到了監管機構的一些反對，到目前為止，他們都接受並理解了該計劃，並且該研究正在世界各地獲得批准，包括日本，我們在那裡與他們舉行了幾次會議，該研究現已在與網站的最終談判中獲得批准，並準備在一個月左右的時間內在日本開始招募。因此，除了更多的監管工作來證明我們還沒有為 III 期研究做好準備之外，沒有任何意外的延遲。

And I just want to say to your point about sites in Eastern Europe. Look, our clinical and regulatory teams have done incredible work here. We had a number of sites that were planned for Belarus, Ukraine and Russia. And in one fell swoop, we lost all those, of course. But we've done a great job finding additional sites, and we are on track with all of those studies, thanks to their work.

我只想對你關於東歐網站的觀點說一下。看，我們的臨床和監管團隊在這裡做了令人難以置信的工作。我們有許多計劃用於白俄羅斯、烏克蘭和俄羅斯的網站。當然，我們一下子就失去了所有這些。但是我們在尋找其他地點方面做得很好，並且由於他們的工作，我們正在按計劃進行所有這些研究。

Our next question comes from Mani Foroohar with SVB Securities.

我們的下一個問題來自 SVB 證券公司的 Mani Foroohar。

I wanted to revisit the topic of (inaudible) couple of times around the pulmonary platform. The clarity you've given around the macrophage overload is really helpful. As you pursue more effective, more potent approaches to allow a lower absolute dose, what metrics will you be tracking? And what will your bar be to disclose further evidence of macrophage activation? Any additional toxicology signals the pop up as you track how effectively or effectively you're threading the needle on delivered dose in macrophage activation?

我想圍繞肺部平台多次重溫（聽不清）這個話題。你對巨噬細胞過載的清晰描述非常有幫助。當您尋求更有效、更有效的方法來降低絕對劑量時，您將跟踪哪些指標？您要披露巨噬細胞激活的進一步證據的標準是什麼？當您跟踪在巨噬細胞激活中輸送劑量時穿針的有效性或有效性，任何額外的毒理學信號都會彈出？

I think we will run -- I think we've already discussed the acute tox results at the Analyst Day a while back. And as a reminder, in the acute IND-enabling or CTA-enabling studies that the top dose was the NOAEL for MUC5AC and for RAGE, and there were no adverse findings in either of those tox studies. And then we will, in the near future, initiate chronic tox studies. As also described during the Analyst Day event, I think we can really spread the doses out in those chronic tox studies. So just overall less exposure, those studies compared to what we did in ENaC. And then in terms of results of those studies, I don't know if we've guided on timing to disclose chronic tox study results.

我想我們會跑——我想我們已經在不久前的分析師日討論了急性毒性結果。提醒一下，在急性 IND 啟用或 CTA 啟用研究中，最高劑量是 MUC5AC 和 RAGE 的 NOAEL，並且在這兩項毒性研究中都沒有不良發現。然後我們將在不久的將來啟動慢性毒性研究。正如在分析師日活動中所描述的那樣，我認為我們真的可以在那些慢性毒物研究中分散劑量。因此，與我們在 ENaC 中所做的相比，這些研究總體上暴露較少。然後就這些研究的結果而言，我不知道我們是否已經指導了披露慢性毒性研究結果的時間。

And it's not generally our -- we generally don't disclose tox results. But as those come in, we will know more about what sort of TI to expect. But we had, I think, some good slides in the Pulmonary R&D Day, where we showed what we believe now is sort of the threshold above which we don't want to go for -- in terms of volume of material. And we feel good that MMP7, MUC5AC and RAGE are substantially below that line. If you look -- if you compare what our expected dosing is, for instance, MUC and RAGE, which are in the clinic now, as you know, compare that to ARO-ENaC, so not only are we providing less drug, but we're also providing it less frequently. That was 3 consecutive days every 2 weeks, and now we're looking at one dose every month or less frequently and a lower dose on top of that. So, we feel good that we can thread this needle. And frankly, I don't think the eye of that needle is terribly narrow. But look, we'll know more as we start to see knockdown and as we see chronic tox data.

這通常不是我們的——我們通常不披露毒性結果。但隨著它們的到來，我們將更多地了解期望的 TI 類型。但我認為，我們在肺部研發日有一些很好的幻燈片，在那裡我們展示了我們現在認為是我們不想超過的閾值——就材料量而言。我們對 MMP7、MUC5AC 和 RAGE 大大低於該線感到滿意。如果你看 - 如果你比較我們的預期劑量，例如，MUC 和 RAGE，如你所知，現在在診所，將其與 ARO-ENaC 進行比較，所以我們不僅提供更少的藥物，而且我們'也不太頻繁地提供它。那是每 2 周連續 3 天，現在我們每個月或更少地觀察一次劑量，在此基礎上觀察更低的劑量。所以，我們感覺很好，我們可以穿這根針。坦率地說，我不認為那根針的眼很窄。但是看，當我們開始看到擊倒和看到慢性毒性數據時，我們會知道更多。

Our next question comes from Mayank Mamtani with B. Riley FBR.

我們的下一個問題來自 Mayank Mamtani 和 B. Riley FBR。

So just a strategic question for ARO-ANG3. So will you wait for the GATEWAY study results before determining next steps for ANG3 on the dyslipidemia indication based on AAT? And the reason I ask is that Lilly has a similar study like AAT listed on clinicaltrials.gov that could make it a very competitive situation now that earlier forms like the antibody or the less safe modality has cleared out. So just curious, will you wait out for your [retro fetch] results?

所以這只是 ARO-ANG3 的一個戰略問題。那麼，您是否會等待 GATEWAY 研究結果，然後再根據 AAT 確定 ANG3 在血脂異常適應症上的下一步？我問的原因是 Lilly 有一項類似的研究，比如在 clinicaltrials.gov 上列出的 AAT，這可能會使它成為一個非常有競爭力的情況，因為早期的形式如抗體或不太安全的方式已經被清除。所以很好奇，你會等待你的 [retro fetch] 結果嗎？

Yes. We have some ideas about what Phase III will look like. But of course, we need to see what those data look like before we design those studies. We feel -- with respect to the competitive question, we feel good about where we sit competitively in terms of our lead with RNAi and certainly over antisense, as well as antibody competitors. But anyway, I guess the short answer is yes. We have a lot of ideas about what a Phase III is going to look like, but we're not going to make any real decisions until we could sit through with the data. But my expectation is that -- well, expectation is a too strong word. We're curious to see if pockets of populations present themselves as a result of this. Do we find certain populations that respond better than others. There's just no substitute for data. So, we'll wait to see that.

是的。我們對第三階段的樣子有一些想法。但是，當然，在我們設計這些研究之前，我們需要看看這些數據是什麼樣子的。我們覺得——關於競爭問題，我們對我們在 RNAi 方面的領先優勢，當然還有反義以及抗體競爭對手方面的競爭地位感到滿意。但無論如何，我想簡短的回答是肯定的。我們對 III 期將是什麼樣子有很多想法，但在我們可以坐下來處理數據之前，我們不會做出任何真正的決定。但我的期望是——好吧，期望是一個過於強烈的詞。我們很想知道是否有一小群人因此而出現。我們是否發現某些人群比其他人群反應更好？數據無可替代。所以，我們拭目以待。

And I would add also that we wouldn't have -- we're not going to have to wait for GATEWAY. So GATEWAY and ARCHES should read out right around the same time. So GATEWAY is an open-label study. ARCHES-2 is fully enrolled, and it will complete right around the end of the year. So, we should have both of those available at the same time.

我還要補充一點，我們不會 - 我們不必等待 GATEWAY。所以 GATEWAY 和 ARCHES 應該大約同時讀出。因此 GATEWAY 是一項開放標籤研究。 ARCHES-2 已全部註冊，並將在今年年底左右完成。所以，我們應該同時擁有這兩個。

Got it. And then on ARO-RAGE, have you disclosed the specific dose levels you're going up during the MAD? Because you say 3 times lower than ENaC, but I don't know how that cuts across absolute dose level and frequency.

知道了。然後在 ARO-RAGE 上，你有沒有透露你在 MAD 期間要上升的具體劑量水平？因為你說比 ENaC 低 3 倍，但我不知道這如何跨越絕對劑量水平和頻率。

I don't think we've disclosed the actual dose levels yet.

我認為我們還沒有透露實際劑量水平。

At the Analyst Day, we presented the study design. So....

在分析師日，我們介紹了研究設計。所以....

We showed -- there was a...

我們展示了——有一個……

I think we did.

我想我們做到了。

There was a slide that showed kind of the magnitude of dose levels in the tox studies, but I don't think there was -- the exact doses weren't disclosed. Yes.

有一張幻燈片顯示了毒性研究中劑量水平的大小，但我認為沒有——確切的劑量沒有被披露。是的。

In any case, the dose frequency is certainly less than what we were doing with ENaC.

無論如何，劑量頻率肯定低於我們對 ENaC 所做的。

Yes. Remember, ENaC was day one, 2, 3, every 2 weeks. And here, it's just one day, every 2 or 4 weeks, right?

是的。請記住，ENaC 是每 2 週的第一天、第二天、第三天。在這裡，它只是一天，每 2 或 4 週一次，對嗎？

Yes. Either the single dose for day one, day 29.

是的。第一天、第 29 天的單劑量。

Day 29, so very different.

第 29 天，非常不同。

Okay. And then my final question. Just curious about the milestone payment structure with the Amgen Lp(a). Is there anything specifically structured around them initiating or along the way of executing a CV outcome study? Is there any milestones associated there?

好的。然後是我的最後一個問題。只是對 Amgen Lp(a) 的里程碑付款結構感到好奇。是否有任何圍繞他們發起或執行 CV 結果研究的特定結構？那裡有任何相關的里程碑嗎？

Unfortunately, we can't give you any guidance on magnitude in milestones or individual triggers. Although I think it would -- I think it's quite common that there is a milestone payment for Phase III initiations.

不幸的是，我們無法為您提供有關里程碑或單個觸發器的大小的任何指導。儘管我認為這會——我認為 III 期啟動的里程碑付款是很常見的。

Got it. Looking forward to learning more about that.

知道了。期待了解更多相關信息。

Our next question comes from Prakhar Agrawal with Cantor.

我們的下一個問題來自 Prakhar Agrawal 和 Cantor。

So, I had 2. First, a clarification on AAT. Is the biopsy sampling and the reading protocol between 202 and Phase II protocol trial similar? Or are there any changes that we should be aware of?

所以，我有 2 個問題。首先，澄清 AAT。 202和II期方案試驗的活檢取樣和讀取方案是否相似？或者有什麼我們應該注意的變化嗎？

And second, on the long-term strategy for the CV portfolio, Chris, recent CV launches continue to be slow even for companies with strong existing infrastructure in this space. Inclisiran had $35 million in sales in first half and Novartis is still working through some of the logistical hurdles. So how much of these are these slow CV launches shaping your view about keeping the different assets in-house versus looking for partners who already have the infrastructure?

其次，關於 CV 產品組合的長期戰略，克里斯最近的 CV 發布仍然緩慢，即使對於在該領域擁有強大現有基礎設施的公司也是如此。 Inclisiran 上半年的銷售額為 3500 萬美元，諾華仍在努力克服一些後勤障礙。那麼這些緩慢的 CV 發布中有多少塑造了您關於將不同資產保留在內部而不是尋找已經擁有基礎設施的合作夥伴的觀點？

So the AAT program, the biopsy assessment is identical for both studies as the 2 pathologists that were trained together to read this. If they agree that at the end of the process, if they disagree, there is a third pathologist to decide which one of the 2 reads is the one that is considered the final read. So that's the procedure. The process is exactly the same. The pathologies are the same. So, I expect a consistent output out of this study.

因此，AAT 程序、活檢評估對於這兩項研究是相同的，因為 2 位病理學家一起接受過培訓來閱讀這篇文章。如果他們同意，在過程結束時，如果他們不同意，則有第三位病理學家來決定 2 個讀數中的哪一個被認為是最終讀數。這就是程序。這個過程是完全一樣的。病理是一樣的。因此，我希望這項研究能夠得出一致的結果。

And regarding our confidence or our willingness to commercialize our CV assets on our own, that hasn't changed for us. Look, we think these are -- we think these are drugs. The data have been consistent. They've been good. I think there are clear places for both of these drug candidates. If you look at triglycerides, look, I think there's increasing evidence that elevated triglycerides at least for some patients are going to affect outcomes and there historically hasn't been a way to modulate triglycerides very much. If you look at fish oils, maybe 18% to maybe 30% reduction, when you compare that to, for instance, APOC3, where we're seeing reductions as high as 90%, sometimes even more than that, where we really move the needle. I think these are big opportunities for us. And I think that -- I think these will have a lot of patients. And so we are as willing as ever to commercialize these on our own.

關於我們自己將 CV 資產商業化的信心或意願，這對我們來說並沒有改變。看，我們認為這些是——我們認為這些是毒品。數據一直一致。他們一直很好。我認為這兩種候選藥物都有明確的位置。如果你看看甘油三酯，看，我認為有越來越多的證據表明，至少對某些患者來說，甘油三酯升高會影響結果，而且歷史上還沒有一種方法可以很好地調節甘油三酯。如果你看看魚油，可能會減少 18% 到 30%，當你將其與 APOC3 進行比較時，我們看到魚油的減少量高達 90%，有時甚至更多，我們真正將針。我認為這些對我們來說是巨大的機會。而且我認為 - 我認為這些會有很多病人。因此，我們一如既往地願意自己將這些產品商業化。

This concludes the Question-and-Answer Session. I would like to turn the conference back over to Chris Anzalone for closing remarks.

問答環節到此結束。我想將會議轉回給 Chris Anzalone 作閉幕詞。

Thanks, everyone, for joining today. We look forward to talking to you again next quarter.

謝謝大家今天的加入。我們期待下個季度再次與您交談。

The conference has now concluded. Thank you for attending today's presentation. You may now disconnect.

會議現已結束。感謝您參加今天的演講。您現在可以斷開連接。