Arrowhead Pharmaceuticals Inc (ARWR) 2022 Q4 法說會逐字稿

Ladies and gentlemen, welcome to 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。

Thank you, Justin. Good afternoon, everyone, and thank you for joining us today to discuss Arrowhead's results for its fiscal 2022 fiscal year ended December (sic) [September] 30, 2022. 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.

謝謝你，賈斯汀。大家下午好，感謝您今天加入我們，討論 Arrowhead 截至 2022 年 12 月（原文如此）[9 月] 30 日的 2022 財年業績。今天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況；我們的首席醫療官 Javier San Martin 博士將提供我們中期和後期臨床管道的最新情況；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。

In addition, Tracie Oliver, our Chief Commercial Officer; and Patrick O'Brien, our Chief Operating Officer and General Counsel, will both be available during the Q&A portion of the call.

此外，我們的首席商務官 Tracie Oliver；我們的首席運營官兼總法律顧問 Patrick O'Brien 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 fact are forward-looking statements and are subject to numerous risks and uncertainties that could cause actual results to differ materially from those expressed in any forward-looking statements.

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。除陳述外的所有陳述歷史事實屬於前瞻性陳述，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存在重大差異。

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.

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 表年度報告和 10-Q 表季度報告。

With that said, I'd like to turn the call over to Chris 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 Chris Anzalone。克里斯？

Thanks, Vince. Good afternoon, everyone, and thank you for joining us today. Quickly, Vince accidently misspoke and he said that our fiscal fourth quarter ended December 30, what he meant was September 30 2020 -- 2022. Our fourth fiscal quarter and period since our last call has been highly productive. We've seen clear progress across our large and balanced pipeline, large because it now includes 12 drug candidates in clinical trials and balanced because it spans in multiple therapeutic areas and includes 6 partnered programs and 6 that are wholly owned.

謝謝，文斯。大家下午好，感謝您今天加入我們。很快，文斯不小心說錯了，他說我們的第四財季結束於 12 月 30 日，他的意思是 2020 年 9 月 30 日——2022 年。自我們上次通話以來，我們的第四財季和期間一直非常富有成效。我們已經看到我們龐大而平衡的管道取得了明顯進展，之所以大，是因為它現在包括 12 種處於臨床試驗中的候選藥物，而平衡是因為它跨越多個治療領域，包括 6 個合作項目和 6 個完全擁有的項目。

It is a good representation of that which makes us different. We are a company built on an increasingly validated technological platform applied to a large number of varied diseases across multiple organ systems where development is uncommonly rapid from idea to the patients in need, and we use targeted disciplined partnering to help finance development of our wholly owned drugs. This is who we are, and these factors are not new. What is new is the growing sense of clarity we are achieving.

這是使我們與眾不同的一個很好的代表。我們是一家建立在日益驗證的技術平台之上的公司，該平台應用於跨多個器官系統的大量不同疾病，從想法到有需要的患者的發展異常迅速，我們使用有針對性的紀律合作夥伴來幫助資助我們全資的發展藥物。這就是我們，這些因素並不新鮮。新的是我們正在實現的越來越清晰的感覺。

I think that this recurring -- I think that this is a recurring theme of this update. We have increased clarity as to the makeup of our multiple Phase III programs, increased clarity as to how we intend to use our late-stage drug candidates in different patient populations, increased clarity as to when we expect proof of concept from our earlier stage programs, increased clarity as to where we plan to go next with the expansion of our platforms into new cell types, increased clarity as to how large we think our pipeline of clinical candidates will be over the next few years and increased clarity about how we intend to finance our growing pipeline.

我認為這是反復出現的——我認為這是本次更新的反復出現的主題。我們更加清楚地了解我們的多個 III 期項目的構成，更加清楚地了解我們打算如何在不同的患者人群中使用我們的後期候選藥物，更加清楚地了解我們何時期望從早期階段的項目中獲得概念證明，隨著我們的平台擴展到新的細胞類型，更加清楚我們下一步計劃去哪裡，更加清楚我們認為我們的臨床候選人管道在未來幾年會有多大，並且更加清楚我們打算如何為我們不斷增長的管道提供資金。

Let's touch on some of these. First, we expect to report on progress for fazirsiran, our AAT program, partnered with Takeda in the near term. We would like to report top line data from the Phase II SEQUOIA study. At the same time, we provide guidance on the Phase III study design. Ideally, Takeda and Arrowhead would do these together. Takeda submitted a Phase III protocol to the U.S. FDA at the end of last quarter and is waiting for feedback. We expect Takeda to receive that feedback shortly if there are any comments at all.

讓我們談談其中的一些。首先，我們預計將在近期報告與武田合作的 AAT 項目 fazirsiran 的進展情況。我們想報告來自第二階段 SEQUOIA 研究的頂線數據。同時，我們對III期研究設計提供指導。理想情況下，武田和 Arrowhead 會一起做這些。武田在上個季度末向美國 FDA 提交了 III 期方案，目前正在等待反饋。如果有任何評論，我們希望 Takeda 能盡快收到該反饋。

We believe the FDA's feedback from prior meetings has been appropriately incorporated into the study design, so we do not expect any major surprises. I believe we have clarity on the future development paths and time lines as well as what the SEQUOIA data are telling us, and we will share that as soon as we can. Second, we are gaining a clear understanding about how our cardiometabolic programs perform in different patient populations and thus are better able to determine the positioning of each. And importantly, the development paths and studies needed to seek approval for various indications.

我們相信 FDA 從之前的會議中得到的反饋已被適當地納入研究設計中，因此我們預計不會出現任何重大意外。我相信我們已經清楚未來的發展路徑和時間線以及 SEQUOIA 數據告訴我們的內容，我們會盡快分享。其次，我們正在清楚地了解我們的心臟代謝計劃在不同患者群體中的表現，從而能夠更好地確定每個計劃的定位。重要的是，尋求各種適應症批准所需的開發路徑和研究。

Javier will talk about this in a moment, but the interim analysis for the SHASTA-2 and MUIR studies of ARO-APOC3 and the ARCHES-2 study of ARO-ANG3, which we presented at AHA and at an analyst investor event shortly thereafter, gave us some critical insights that are helping to accelerate the path to Phase III studies. We are working on determining the optimal paths, and we expect to have further clarity, including from multiple anticipated regulatory interactions in 2023.

Javier 稍後會談到這一點，但是我們在 AHA 和隨後不久的分析師投資者活動中介紹了 ARO-APOC3 的 SHASTA-2 和 MUIR 研究以及 ARO-ANG3 的 ARCHES-2 研究的中期分析，給了我們一些重要的見解，有助於加快 III 期研究的進程。我們正在努力確定最佳路徑，我們希望進一步明確，包括 2023 年的多項預期監管互動。

At present, we plan to pursue studies to enable us to treat patients with homozygous familial hypercholesterolemia, or HoFH, and heterozygous familial hypercholesterolemia, or HeFH with ARO-ANG3. We hope this would enable us to pursue a staged commercial strategy, whereby we could serve the small HoFH market first and grow into the HeFH market after those larger studies are complete and supplemental regulatory approval is obtained. For ARO-APOC3, we are conducting studies now to enable us to treat FCS patients, followed by treating patients with severe hypertriglyceridemia and eventually the broad population with mixed dyslipidemia.

目前，我們計劃開展研究，使我們能夠用 ARO-ANG3 治療純合子家族性高膽固醇血症 (HoFH) 和雜合子家族性高膽固醇血症 (HeFH) 患者。我們希望這將使我們能夠實施分階段的商業戰略，從而我們可以首先服務於小型 HoFH 市場，並在完成較大的研究並獲得補充監管批准後發展到 HeFH 市場。對於 ARO-APOC3，我們現在正在進行研究，使我們能夠治療 FCS 患者，然後治療嚴重的高甘油三酯血症患者，最終治療患有混合性血脂異常的廣大人群。

As with the HoFH-to-HeFH approach, we like the staged commercial strategy and hope we can serve a small FCS market rather quickly and expand to the larger SHTG population and eventually the even larger mixed dyslipidemia populations when those studies are complete and their respective supplemental regulatory approvals are obtained.

與 HoFH-to-HeFH 方法一樣，我們喜歡分階段的商業策略，並希望我們能夠相當快地服務於一個小的 FCS 市場，並擴展到更大的 SHTG 人群，並最終在這些研究完成時擴大到更大的混合性血脂異常人群和他們各自的獲得補充監管批准。

Third, we have line of sight on time lines for initial interim clinical results for 2 of our pulmonary programs. James will give details on the status, but ARO-RAGE and ARO-MUC5AC are progressing well, and we anticipate being able to provide interim data publicly in the first half of 2023.

第三，我們對我們的 2 個肺部項目的初步中期臨床結果的時間表有了預期。 James 將提供詳細的狀態，但 ARO-RAGE 和 ARO-MUC5AC 進展順利，我們預計能夠在 2023 年上半年公開提供中期數據。

Should we have data that provides clinical proof of concept, I think this would be a potentially big derisking event for the candidates and for the pulmonary platform generally. We believe we've made a lot of progress with the platform since our generation 1 candidate ARO-ENaC and gaining clarity on how the generation 2 candidates perform will be exciting. Importantly, we are performing various analysis to assess pharmacodynamics using different methods. So we are confident that we should be able to define knockdown and duration of effect at different dose levels at different time points.

如果我們有提供臨床概念證明的數據，我認為這對於候選人和肺部平台來說可能是一個潛在的大風險事件。我們相信，自從我們的第 1 代候選人 ARO-ENaC 以來，我們在該平台上取得了很大進展，並且清楚地了解第 2 代候選人的表現將是令人興奮的。重要的是，我們正在進行各種分析，以使用不同的方法評估藥效學。所以我們有信心我們應該能夠定義不同時間點不同劑量水平下的擊倒和效果持續時間。

The ARO-MMP7 Phase I started later than ARO-RAGE and ARO-MUC5AC, but dosing healthy volunteers should begin imminently. Fourth, our ARO-C3 program continues to progress well, and we expect to have interim knockdown and safety data in the first half of 2023. This is an important program for us because: a, the squarely in our wheelhouse as an hepatocyte target; and b, because of the variety of opportunities we can pursue in various complement-mediated and complement-associated diseases.

ARO-MMP7 Phase I 比 ARO-RAGE 和 ARO-MUC5AC 開始得晚，但應該立即開始對健康志願者進行給藥。第四，我們的 ARO-C3 計劃繼續進展順利，我們預計將在 2023 年上半年獲得中期敲低和安全數據。這對我們來說是一個重要的計劃，因為： b，因為我們可以在各種補體介導和補體相關疾病中尋求各種機會。

Fifth, we continue to expand our platform into new cell types and have made enough progress to give us line of sight as to when we can discuss one of them publicly. I expect to provide guidance about our next cell type and initial targets by the end of the first half of 2023. Our goal is to continually expand our platform to gain access to a new cell type every 18 to 24 months. So far, we are ahead of that goal, and you should be hearing more about the work that has gone into the newest cell type and the encouraging preclinical results we are generating.

第五，我們繼續將我們的平台擴展到新的細胞類型，並且已經取得了足夠的進展，讓我們知道何時可以公開討論其中的一種。我希望在 2023 年上半年結束前就我們的下一個細胞類型和初始目標提供指導。我們的目標是不斷擴展我們的平台，每 18 到 24 個月獲得一種新的細胞類型。到目前為止，我們已經領先於該目標，您應該會聽到更多關於最新細胞類型的工作以及我們正在產生的令人鼓舞的臨床前結果。

Sixth, we have a good idea about how large we think we can grow our pipeline in the near to midterm and are announcing our 20 in '25 program. We plan to have 20 individual drug candidates in clinical trials are in the market in 2025. Between our hepatocyte-directed programs, our pulmonary programs, potential skeletal muscle-targeted programs and new cell types, we believe we will hit 20 in the year 2025 between wholly owned drug candidates and partner programs. This will be a remarkable achievement that has the potential to touch millions of lives and create substantial value.

第六，我們很清楚我們認為我們可以在近期和中期擴大我們的管道有多大，並且正在宣布我們的 20 in '25 計劃。我們計劃在 2025 年有 20 種臨床試驗候選藥物上市。在我們的肝細胞定向項目、我們的肺部項目、潛在的骨骼肌靶向項目和新細胞類型之間，我們相信我們將在 2025 年達到 20 個在全資候選藥物和合作夥伴項目之間。這將是一項了不起的成就，有可能觸動數百萬人的生命並創造巨大的價值。

Seventh, we have better clarity about our financial resources. We currently have partnerships with 5 different companies, and we expect to receive milestone payments from each over the next 12 months. Further, our expanding platforms give us the ability to continue to do new business development deals that could continue to provide capital to fund our own programs.

第七，我們更加清楚我們的財務資源。我們目前與 5 家不同的公司建立了合作夥伴關係，我們希望在未來 12 個月內收到每家公司的里程碑付款。此外，我們不斷擴展的平台使我們能夠繼續進行新的業務開發交易，這些交易可以繼續提供資金來資助我們自己的項目。

Notwithstanding access to capital via these means, we recently decided to sell the potential royalties we would receive from Amgen on future olpasiran sales to Royalty Pharma. We received $250 million in cash upfront and up to $160 million in additional payments contingent on the achievement of certain clinical, regulatory and sales milestones. In addition, we retained rights to $400 million in development, regulatory and sales milestone payments potentially due from Amgen from the 2016 license agreement.

儘管通過這些方式獲得了資金，但我們最近決定將我們將從安進公司獲得的未來 olpasiran 銷售的潛在特許權使用費出售給 Royalty Pharma。我們收到了 2.5 億美元的預付現金和高達 1.6 億美元的額外付款，這取決於某些臨床、監管和銷售里程碑的實現。此外，根據 2016 年的許可協議，我們保留了 Amgen 可能應付的 4 億美元開發、監管和銷售里程碑付款的權利。

We have been very impressed with the data from the program, and we are confident that it has the potential to be an important medicine. However, the next step in development is a cardiovascular outcome study that will not read out for multiple years. So it made sense for us to monetize the potential stream of future royalties. This allows us to continue investing in our wholly owned programs, which we think are advancing rapidly to our potential commercialization and also continue to invest in our expanding pipeline and platform technology.

該項目的數據給我們留下了深刻的印象，我們相信它有可能成為一種重要的藥物。然而，下一步的發展是一項心血管結果研究，該研究將在多年內不會被宣讀出來。因此，我們將未來的潛在版稅流貨幣化是有意義的。這使我們能夠繼續投資我們的全資項目，我們認為這些項目正在迅速推進我們的潛在商業化，並繼續投資於我們不斷擴大的管道和平台技術。

Our overarching goal is to bring important medicines to patients as quickly as possible. I believe there are 2 critical interrelated pieces to that: one, develop and commercialize some drugs ourselves; and two, substantially increase our market capitalization so we can do more of number 1. That is the price we need to keep our eye on. So every decision we consider should be made by asking ourselves if it gets us closer to or farther from that goal. In my mind, the decision to sell these future royalties clearly gets us closer to that goal.

我們的首要目標是盡快為患者提供重要藥物。我認為這有兩個關鍵的相互關聯的部分：第一，我們自己開發和商業化一些藥物；第二，大幅增加我們的市值，這樣我們就可以做更多的第一件事。這是我們需要關注的價格。因此，我們考慮的每一個決定都應該通過問自己是否讓我們更接近或更遠離那個目標來做出。在我看來，出售這些未來特許權使用費的決定顯然讓我們更接近那個目標。

With that overview, I'd 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. I want to give updates on 2 main areas of our late-stage development efforts. First, on our cardiometabolic pipeline and second, on fazisiran formerly called ARO-AAT and TAK-999. Earlier this month, data was presented on all 3 of our cardiometabolic programs, ARO-APOC3, ARO-ANG3 and olpasiran at the American Heart Association Scientific Sessions 2022, and a virtual analyst and investor event that we hosted a couple of days after the AHA.

謝謝克里斯，大家下午好。我想介紹我們後期開發工作的兩個主要領域的最新情況。首先，在我們的心臟代謝管道上，其次，在以前稱為 ARO-AAT 和 TAK-999 的 fazisiran 上。本月早些時候，我們在 2022 年美國心臟協會科學會議上展示了我們所有 3 個心臟代謝項目 ARO-APOC3、ARO-ANG3 和 olpasiran 的數據，以及我們在 AHA 之後幾天舉辦的虛擬分析師和投資者活動.

It was a very comprehensive review of the data and our plans for the program. So if you want to hear more from us and from external key opinion leaders in the cardiometabolic space, you can listen to a replay of the webcast or view the presentation slides, both are available on the Arrowhead website.

這是對數據和我們計劃的非常全面的審查。因此，如果您想從我們和心臟代謝領域的外部關鍵意見領袖那裡聽到更多信息，您可以收聽網絡廣播的重播或查看演示幻燈片，兩者都可以在 Arrowhead 網站上找到。

Today, I want to give some context about why we perform an interim analysis, highlight some of the important results and provide guidance on where we see the progress going in the future.

今天，我想介紹一下我們進行中期分析的原因，強調一些重要的結果，並就我們未來的進展方向提供指導。

Chris mentioned earlier that we are gaining clarity across multiple programs, and this is a key point, especially for the cardiometabolic programs. We will now have more clarity on how each of the candidates performed in various patient populations and importantly, where we should focus late-stage developments.

克里斯早些時候提到，我們正在跨多個項目獲得清晰度，這是一個關鍵點，特別是對於心臟代謝項目。我們現在將更清楚地了解每個候選藥物在不同患者群體中的表現，重要的是，我們應該將後期開發的重點放在何處。

So let me start with context on the interim analysis that led to the American High Association presentation. Our wholly owned cardiometabolic candidates, ARO-APOC3 and ARO-ANG3, each target different gene based on human genetic studies, preclinical animal model, each affect lipid and lipoprotein levels in different ways. Remember that we have data from different patient population in the completed Phase I/II studies and multiple additional clinical studies going on now for each program. For ARO-APOC3, we have the following stats: the SHASTA-2 Phase II study in patients with severe hypertriglyceridemia, the new Phase II study in patients with mixed dyslipidemia and the PALISADE Phase III in patients with familial chylomicronemia syndrome.

因此，讓我從導緻美國高級協會演講的中期分析的背景開始。我們全資擁有的心臟代謝候選藥物 ARO-APOC3 和 ARO-ANG3，根據人類遺傳學研究、臨床前動物模型，各自針對不同的基因，各自以不同的方式影響脂質和脂蛋白水平。請記住，我們在已完成的 I/II 期研究中有來自不同患者群體的數據，並且每個項目現在正在進行多項額外的臨床研究。對於 ARO-APOC3，我們有以下統計數據：嚴重高甘油三酯血症患者的 SHASTA-2 II 期研究、混合性血脂異常患者的新 II 期研究以及家族性乳糜微粒血症患者的 PALISADE III 期研究。

For ARO-ANG3, we have the following studies: the ARCHES-2 Phase II study in patients with mixed dyslipidemia and the GATEWAY Phase II in patients with homozygous familial hypercholersterolemia. We combined with the Phase I data within these studies give us a good feature of how the different candidates may affect lipid -- lipoproteins levels and thus which patient populations we should focus on for each. Therefore, the interim analysis enabled us to start the important work required to prepare for Phase III studies. This includes dosing interval, patient population selection, length of the study, modeling to estimate event rates and effect size, registration path and Phase III designs, and where and how to execute these studies.

對於 ARO-ANG3，我們有以下研究：針對混合性血脂異常患者的 ARCHES-2 II 期研究和針對純合子家族性高膽固醇血症患者的 GATEWAY II 期研究。我們與這些研究中的第一階段數據相結合，為我們提供了一個很好的特徵，說明不同的候選人如何影響脂質——脂蛋白水平，因此我們應該關注哪些患者群體。因此，中期分析使我們能夠開始為 III 期研究做準備所需的重要工作。這包括給藥間隔、患者人群選擇、研究長度、估計事件發生率和效應大小的建模、註冊路徑和 III 期設計，以及在哪里以及如何執行這些研究。

We essentially gave ourselves a 6-month head start on all that work. This is critical since we plan on having multiple annual Phase II meeting and moving forward with multiple Phase III studies over the next 12 months.

我們基本上為所有這些工作提前了 6 個月。這一點至關重要，因為我們計劃在未來 12 個月內召開多次年度 II 期會議並推進多項 III 期研究。

Next, I want to highlight some of the key results from the Phase II study that we presented at the American Heart Association and our webcast event. ARO-APOC3, ARO-ANG3 and all olpasiran were all highly active at silencing their respective gene targets, which resulted in encouraging changes in multiple relevant lipids and lipoprotein levels.

接下來，我想重點介紹我們在美國心臟協會和我們的網絡直播活動中展示的 II 期研究的一些關鍵結果。 ARO-APOC3、ARO-ANG3 和所有 olpasiran 在沉默各自的基因靶點方面都非常活躍，這導致多種相關脂質和脂蛋白水平發生令人鼓舞的變化。

In the SHASTA-2 study in subjects with severe hypertriglyceridemia, who had baseline triglycerides or TG greater than 500 milligrams per deciliter treatment with ARO-APOC3 at doses of 10 milligrams, 25 milligrams and 50 milligrams, all durable decrease APOC3 up to 87%, TGs up to 86%, non-HDL up to 45% and increased HDL cholesterol up to 99% through the week 16 time point. ARO-APOC3 has been well tolerated with treatment emergent adverse events reported today that reflect the underlying comorbidities and conditions of the population under study.

在 SHASTA-2 研究中，基線甘油三酯或 TG 大於 500 毫克/分升的重度高甘油三酯血症受試者接受劑量為 10 毫克、25 毫克和 50 毫克的 ARO-APOC3 治療後，所有受試者的 APOC3 均持續降低高達 87%，在第 16 週的時間點，TG 高達 86%，非 HDL 高達 45%，HDL 膽固醇增加高達 99%。 ARO-APOC3 的耐受性良好，今天報告的治療緊急不良事件反映了研究人群的潛在合併症和狀況。

The MUIR study in subject with mixed dyslipidemia, who had an average TG of 220 million per deciliter, non-HDL of 150, LDL cholesterol of 110 and ApoB of 95, remnant cholesterol of 46, and HCL cholesterol of 42 mg per deciliter. Treatment with ARO-APOC3 have doses of 10 mg, 25 milligrams and 50 milligrams resulted in substantial reduction of APOC3 of 80%, TGs of 65%, non-HDL cholesterol of 25%, LDL cholesterol of 20% and ApoB 20%, remnant cholesterol decreased by 60% and HDL cholesterol increased by 50%. We believe these changes all represent key reduction in residual cardiovascular disease risk.

MUIR 研究對象為混合性血脂異常，平均 TG 為 2.2 億/分升，非 HDL 為 150，LDL 膽固醇為 110，ApoB 為 95，殘餘膽固醇為 46，HCL 膽固醇為 42 毫克/分升。用劑量為 10 毫克、25 毫克和 50 毫克的 ARO-APOC3 治療導致 APOC3 顯著降低 80%、TG 降低 65%、非 HDL 膽固醇降低 25%、LDL 膽固醇降低 20% 和 ApoB 降低 20%，殘餘膽固醇降低了 60%，HDL 膽固醇升高了 50%。我們相信這些變化都代表了殘留心血管疾病風險的關鍵降低。

In ARCHES-2 study in subject with mixed dyslipidemia, who had baseline median TG of 226 milligrams per deciliter treatment with ARO-ANG3 at doses of 50 milligrams, 100 milligrams or 200 milligrams, resulted in a substantial reduction of ANGPTL3 up to 71% at week 8, TGs up to 59% at week 16 and LDL cholesterol up to 32% at week 16. ARO-ANG3 was also associated with median relative reduction in liver fat fraction at week 24 of 28% for the 100 and 200-milligram dose with no adverse event related to liver function tests changes reported to date. ARO-ANG3 has been well tolerated day with treatment emergent adverse event reported to date, consistent with those expected in this patient population and with associated underlying comorbidities.

在 ARCHES-2 研究中，患有混合性血脂異常的受試者基線中位 TG 為 226 毫克/分升，接受劑量為 50 毫克、100 毫克或 200 毫克的 ARO-ANG3 治療後，ANGPTL3 顯著降低高達 71%第 8 週，TG 在第 16 周高達 59%，LDL 膽固醇在第 16 周高達 32%。對於 100 和 200 毫克劑量，ARO-ANG3 還與第 24 週肝脂肪分數中值相對降低 28% 相關迄今為止沒有報告與肝功能測試變化相關的不良事件。 ARO-ANG3 的耐受性良好，迄今為止報告了治療中出現的不良事件，與該患者群體中預期的不良事件以及相關的潛在合併症一致。

Amgen also presented enough treatment data from its Phase II OCEAN A dose study of olpasiran in adults with elevate lipoprotein(a) level greater than 150-nanomoles per liter in a history of atherosclerotic cardiovascular disease. These data were also published in the New England Journal of Medicine.

Amgen 還提供了來自其 II 期 OCEAN A 劑量研究的足夠治療數據，該研究在有動脈粥樣硬化性心血管疾病病史的成人中脂蛋白 (a) 水平升高超過 150 納摩爾/升。這些數據也發表在《新英格蘭醫學雜誌》上。

Placebo-adjusted mean percent reduction of Lp(a) were 70.5% for patients receiving 10 milligrams every 12 weeks, 97.4% for patients receiving 75 milligrams every 12 weeks, 101.1% for patients receiving 225 milligrams every 12 weeks and 100.5% for patients receiving 225 milligrams every 24 weeks. The totality of these data demonstrate the significant progress achieving RNAi drug development specifically, which is a potential future treatment paradigm where Arrowhead's proprietary TRiM technology may be permanently leveraged in preventive cardiology.

每 12 週接受 10 毫克治療的患者經安慰劑調整後的 Lp(a) 平均降低百分比為 70.5%，每 12 週接受 75 毫克治療的患者為 97.4%，每 12 週接受 225 毫克治療的患者為 101.1%，接受治療的患者為 100.5%每 24 週 225 毫克。這些數據的整體表明，具體來說，實現 RNAi 藥物開發取得了重大進展，這是一種潛在的未來治療範式，Arrowhead 的專有 TRiM 技術可能會永久用於預防心髒病學。

So what do we do with ARO-APOC3 and ARO-ANG3. For ARO-ANG3, we're focusing on patient with hypercholersterolemia. ANGPTL3 Is a key regulator of lipid and lipoprotein metabolism that inhibits lipoprotein lipase and endothelial lipase. ARO-ANG3 has a unique mechanical function to address hypercholersterolemia distinct from other LDL cholesterol lowering therapies. It may address unmet need in patients with specific genetic mutation, for example, patients with dysfunctional LDL receptors. It may also be added to other LDL cholesterol-lowering therapies in patients not reaching (inaudible).

那麼我們如何處理 ARO-APOC3 和 ARO-ANG3。對於 ARO-ANG3，我們專注於高膽固醇血症患者。 ANGPTL3 是抑制脂蛋白脂肪酶和內皮脂肪酶的脂質和脂蛋白代謝的關鍵調節劑。 ARO-ANG3 具有獨特的機械功能來解決高膽固醇血症，這與其他低密度脂蛋白膽固醇降低療法不同。它可以解決具有特定基因突變的患者未滿足的需求，例如，LDL 受體功能障礙的患者。對於未達到（聽不清）的患者，它也可以添加到其他低密度脂蛋白膽固醇降低療法中。

Patients with heterozygous familial hypercholesterolemia or HeFH, typically have LDL cholesterol greater than 190 milligrams per deciliter and have increased rates of ASCVD. They are estimated to be around 1.4 million patients in the U.S. with HeFH. Patients with homozygous familial hypercholersterolemia or HoFH, typically have LDL cholesterol greater than 400 milligrams per deciliter. There are around 1,200 patients with HoFH in the U.S. These are the 2 indications that we're focusing on initially for ARO-ANG3. Our plan is to have annual Phase II meeting in the first half of 2023 and then potentially begin Phase III studies in the second half of 2023.

雜合子家族性高膽固醇血症或 HeFH 患者的 LDL 膽固醇通常大於 190 毫克/分升，並且 ASCVD 發生率增加。據估計，美國約有 140 萬 HeFH 患者。純合子家族性高膽固醇血症或 HoFH 患者的 LDL 膽固醇通常大於 400 毫克/分升。美國大約有 1,200 名 HoFH 患者。這些是我們最初關注 ARO-ANG3 的兩個適應症。我們的計劃是在 2023 年上半年舉行年度 II 期會議，然後可能在 2023 年下半年開始 III 期研究。

We view ARO-APOC3 as having potentially a broader set of indications and patient population where it might provide a benefit. It potentially address the risk of bronchiectasis in severe hypertriglyceridemia syndrome. ARO-APOC3 also modulates multiple lipids and lipoproteins that contribute to the residual risk of cardiovascular in patients with mixed dyslipidemia, which has the potential to translate into a decrease in atherosclerosis and coronary disease progression.

我們認為 ARO-APOC3 可能具有更廣泛的適應症和可能提供益處的患者群體。它可能解決嚴重高甘油三酯血症綜合徵中支氣管擴張的風險。 ARO-APOC3 還調節多種脂質和脂蛋白，這些脂質和脂蛋白有助於混合性血脂異常患者心血管的殘餘風險，這有可能轉化為減少動脈粥樣硬化和冠心病進展。

ARO-APOC3 is a key regulator of lipid and lipoprotein metabolism that inhibit lipoprotein lipase and mediates hepatic uptake of remnants particles in the LPL-independent pathway. ARO-APOC3 improves multiple lipid parameters that may provide clinical benefit in a broad population with dyslipidemia. In clinical studies, it has reduced TL in patients with severe hypertriglyceridemia, including FCS, which has the potential to decrease the risk of acute pancreatitis.

ARO-APOC3 是脂質和脂蛋白代謝的關鍵調節因子，可抑制脂蛋白脂肪酶並介導 LPL 非依賴性途徑中殘餘顆粒的肝臟攝取。 ARO-APOC3 改善了多種脂質參數，可能為廣大血脂異常人群提供臨床益處。在臨床研究中，它降低了包括 FCS 在內的嚴重高甘油三酯血症患者的 TL，這有可能降低急性胰腺炎的風險。

It has also reduced multiple residual cardiovascular risk factors such as APOC3, LDL cholesterol, ApoB, remnant cholesterol and others in patient at risk of ASCVD. We're already conducting the PALISADE Phase III study of ARO-APOC3 in patients with FCS, which is approximately 50% enrolled at this time. Our plan for the additional indication is to have regulatory interactions in the second half of 2023 and begin Phase III studies in the first half of 2024. These additional indications are SHTG with a prevalence of around 4 million in the U.S. and patients at risk for ASCVD despite maximal tolerate statins with a prevalence of around 12 million in the U.S.

它還降低了存在 ASCVD 風險的患者的多種殘餘心血管危險因素，如 APOC3、LDL 膽固醇、ApoB、殘餘膽固醇和其他因素。我們已經在 FCS 患者中進行 ARO-APOC3 的 PALISADE III 期研究，目前大約有 50% 的患者入組。我們對額外適應症的計劃是在 2023 年下半年進行監管互動，並在 2024 年上半年開始 III 期研究。這些額外適應症是 SHTG，在美國患病率約為 400 萬，患者有 ASCVD 風險儘管最大耐受他汀類藥物在美國的流行率約為 1200 萬

Now I want to move on to fazirsiran, our investigational RNAi therapeutic designed to reduce production of mutant from the alpha-1 antitrypsin protein called Z-AAT. The potential treatment for the rare genetic liver is associated with alpha-1 antitrypsin deficiency. Z-AAT accumulation is believed to be the cause of progressive liver disease in patients with AAT deficiency. Production of the pro-inflammatory Z-AAT protein has the potential to halt the progression of liver disease and potentially allow the liver to regenerate and repair.

現在我想繼續介紹 fazirsiran，我們的研究性 RNAi 療法旨在減少 alpha-1 抗胰蛋白酶蛋白 Z-AAT 突變體的產生。罕見遺傳性肝臟的潛在治療方法與 α-1 抗胰蛋白酶缺乏症有關。 Z-AAT 積累被認為是 AAT 缺乏症患者進行性肝病的原因。促炎性 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。

Data from our label -- our open-label Phase II study were published earlier this year in the New England Journal of Medicine. Those data suggested that fazirsiran was very effective at reducing the production of the Z-AAT protein and that delivers of this patient were able to begin the process of healing. This includes breaking down and cleaning the accumulated Z-AAT in the liver, decreasing the histologic global burden, demonstrating histologic improvement in inflammation, reducing biomarkers of liver injury and ultimately decrease fibrosis severity. These were very encouraging signs for the potential of fazirsiran to help patients with AATD liver disease.

來自我們標籤的數據——我們的開放標籤 II 期研究已於今年早些時候發表在《新英格蘭醫學雜誌》上。這些數據表明，fazirsiran 在減少 Z-AAT 蛋白的產生方面非常有效，並且該患者的分娩能夠開始癒合過程。這包括分解和清除肝臟中積累的 Z-AAT，降低組織學整體負擔，證明炎症的組織學改善，減少肝損傷的生物標誌物並最終降低纖維化的嚴重程度。這些都是非常令人鼓舞的跡象，表明 fazirsiran 具有幫助 AATD 肝病患者的潛力。

We now look to the fazirsiran Phase II placebo-controlled SEQUOIA study and to regulatory interactions on the Phase III study. The SEQUOIA data are mostly in now, and we're waiting to receive feedback, if any, from the FDA on the proposed design for the Phase III study. These are expected soon. So we are -- we and our partner at Takeda, will together determine the best way to communicate this publicly.

我們現在關注 fazirsiran II 期安慰劑對照的 SEQUOIA 研究和 III 期研究的監管相互作用。 SEQUOIA 數據現在大部分已經完成，我們正在等待 FDA 對 III 期研究的擬議設計的反饋（如果有的話）。這些預計很快就會出現。所以我們——我們和我們在武田的合作夥伴，將共同確定公開交流這一點的最佳方式。

Takeda is still on schedule to begin the Phase III study in the first quarter of 2023. And we're confident that we can have an update publicly on SEQUOIA and guidance on the Phase III prior to that.

武田仍按計劃在 2023 年第一季度開始 III 期研究。我們有信心在此之前公開更新 SEQUOIA 和 III 期指南。

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？

Thank you, Javier. I want to give updates on 4 of our earlier-stage programs that include 3 pulmonary candidates, targeting RAGE, MUC5AC and MMP7, and on our candidate targeting complement C3.

謝謝你，哈維爾。我想介紹我們早期階段的 4 個項目的最新情況，其中包括 3 個針對 RAGE、MUC5AC 和 MMP7 的肺候選藥物，以及我們的候選藥物靶向補體 C3。

Let's start with C3. ARO-C3 is an investigational RNAi therapeutic designed to reduce hepatocyte expression of complement component 3 or C3 as a potential therapy for various complement-mediated hematologic and renal diseases.

讓我們從 C3 開始。 ARO-C3 是一種研究性 RNAi 療法，旨在降低補體成分 3 或 C3 的肝細胞表達，作為各種補體介導的血液病和腎臟疾病的潛在療法。

We are conducting a Phase I/II clinical study now that includes 2 parts. Part 1 is placebo-controlled and healthy volunteers and include single ascending dose or SAD cohorts and multiple ascending dose or MAD cohorts. All of the SAD and MAD cohorts are fully enrolled and participants are being followed to assess safety and tolerability, dose response based on serum C3 levels, and duration of effect at various dose levels. We are confident that we will have sufficient data in the first half of 2023 to report interim results from Part 1 of the study.

我們現在正在進行 I/II 期臨床研究，包括 2 個部分。第 1 部分是安慰劑對照和健康志願者，包括單次遞增劑量或 SAD 隊列和多次遞增劑量或 MAD 隊列。所有 SAD 和 MAD 隊列都已完全註冊，並且正在跟踪參與者以評估安全性和耐受性、基於血清 C3 水平的劑量反應以及不同劑量水平的效果持續時間。我們相信，我們將在 2023 年上半年獲得足夠的數據來報告該研究第 1 部分的中期結果。

Part 2 is open label in eligible subjects with paroxysmal nocturnal hemoglobinuria, or PNH, and complement-mediated renal diseases, including IgA nephropathy and C3 glomerulopathy. Data from Part 1 will inform Part 2 dose selection, which we expect to happen in the coming months, and then the patient cohorts will be open for enrollment in the first half of 2023.

第 2 部分在患有陣發性睡眠性血紅蛋白尿 (PNH) 和補體介導的腎臟疾病（包括 IgA 腎病和 C3 腎小球病）的合格受試者中是開放標籤的。第 1 部分的數據將為第 2 部分的劑量選擇提供信息，我們預計這將在未來幾個月內完成，然後患者隊列將在 2023 年上半年開放註冊。

We are very excited about this program and believe it has the potential to address multiple serious complement mediated or complement-associated diseases with unmet need in the renal and hematologic spaces. We know that complement C5 inhibitors are disease-modifying in conditions such as PNH and believe that proximal C3 inhibition may confer advantages over C5 blockade. For example, C5 monoclonal antibodies only block the terminal complement pathway and many of the proximal complement actions remain intact. In addition, clinical validation exists for C3 inhibitors, and we believe RNAi-based C3 inhibition could have clear dosing advantages over other mechanisms.

我們對這個項目感到非常興奮，並相信它有可能解決多種嚴重的補體介導或補體相關疾病，而這些疾病在腎臟和血液領域的需求未得到滿足。我們知道補體 C5 抑製劑在 PNH 等病症中可以改善疾病，並且相信近端 C3 抑制可能比 C5 阻斷具有優勢。例如，C5 單克隆抗體僅阻斷末端補體通路，許多近端補體作用保持完整。此外，C3 抑製劑存在臨床驗證，我們相信基於 RNAi 的 C3 抑制可能比其他機制具有明顯的劑量優勢。

Furthermore, alternative pathway inhibition is likely of key relevance for treatment of conditions such as IgA nephropathy, C3 glomerulopathy and potentially other glomerular diseases. ARO-C3 is a subcutaneously administered candidate with an expected long dosing interval of once every 3 months or less frequent. We think this would be much more patient friendly than current C3 inhibitors that require a high volume infusion multiple times per week.

此外，替代途徑抑制可能與 IgA 腎病、C3 腎小球病和其他潛在腎小球疾病等病症的治療具有關鍵相關性。 ARO-C3 是一種皮下給藥的候選藥物，預期的長給藥間隔為每 3 個月一次或更少。我們認為這比目前需要每週多次大量輸注的 C3 抑製劑對患者更友好。

I will now move on to our 3 pulmonary candidates starting with ARO-MMP7. ARO-MMP7 is designed to reduce expression of matrix metalloproteinase 7 or MMP7 as a potential treatment for idiopathic fibrosis or IPF. MMP7 is thought to play 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 preserve pulmonary function. In August, we filed a CTA to begin a Phase I/II clinical study of ARO-MMP7. The Phase I/II study will be similar in design to our other first-in-human studies and includes a healthy volunteer portion followed by a patient portion.

我現在將從 ARO-MMP7 開始介紹我們的 3 個肺部候選藥物。 ARO-MMP7 旨在減少基質金屬蛋白酶 7 或 MMP7 的表達，作為特發性纖維化或 IPF 的潛在治療方法。 MMP7 被認為在 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、限制肺纖維化並保護肺功能。 8 月，我們提交了 CTA 以開始 ARO-MMP7 的 I/II 期臨床研究。 I/II 期研究在設計上將與我們的其他首次人體研究相似，包括健康志願者部分和隨後的患者部分。

Now moving on to our 2 other pulmonary programs, ARO-MUC5AC and ARO-RAGE, our investigational RNAi therapeutics designed to reduce production of mucin 5AC or MUC5AC and the receptor for advanced glycation end products or RAGE, respectively, as potential treatments for various muco-obstructive and inflammatory pulmonary diseases.

現在繼續我們的其他 2 個肺部計劃，ARO-MUC5AC 和 ARO-RAGE，我們的研究性 RNAi 療法旨在分別減少粘蛋白 5AC 或 MUC5AC 和晚期糖基化終產物或 RAGE 的受體的產生，作為各種粘液的潛在治療方法- 阻塞性和炎症性肺部疾病。

These 2 programs are on largely parallel paths and at approximately the same stage. They are both in Phase I/II studies designed to assess safety and tolerability, pharmacokinetics and pharmacodynamics in healthy volunteers first and then in patients with asthma. For both programs, we are approaching full enrollment of the healthy volunteer SAD cohorts and are well into enrollment of the healthy volunteer MAD cohorts. In both the SAD and MAD, we have various methods to assess target engagement, including induced sputum and bronchoalveolar lavage fluid.

這兩個項目在很大程度上處於平行路徑上，並且處於大致相同的階段。它們都處於 I/II 期研究中，旨在首先評估健康志願者的安全性和耐受性、藥代動力學和藥效學，然後再評估哮喘患者。對於這兩個項目，我們正在接近健康志願者 SAD 隊列的全面註冊，並且正在順利註冊健康志願者 MAD 隊列。在 SAD 和 MAD 中，我們有多種方法來評估目標參與度，包括誘導痰和支氣管肺泡灌洗液。

And for RAGE, we are also measuring serum sRAGE protein, a circulating biomarker for RAGE target engagement in the lung. We anticipate that we will be able to report interim results from Phase -- from Part 1 of these studies and begin Part 2 in patients with asthma in the first half of 2023.

對於 RAGE，我們還在測量血清 sRAGE 蛋白，這是一種循環生物標誌物，用於 RAGE 靶標在肺部的參與。我們預計我們將能夠報告階段的中期結果——這些研究的第 1 部分，並在 2023 年上半年開始對哮喘患者進行第 2 部分。

These are potentially important new medicines that address targets that have been difficult to drug with other modalities and are designed to treat muco-obstructive and inflammatory lung diseases in fundamentally new ways.

這些潛在的重要新藥可解決難以用其他方式給藥的靶標，旨在以全新的方式治療粘液阻塞性和炎症性肺病。

We are excited to see and share these results, and we are confident in the progress we've made on our pulmonary TRiM platform and these 2 -- these generation 2 candidates.

我們很高興看到並分享這些結果，我們對我們在肺部 TRiM 平台和這兩個——這些第 2 代候選人上取得的進展充滿信心。

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. As we reported today, our net loss for fiscal 2022 was $176.1 million or $1.67 per share based on 105.4 million fully diluted weighted average shares outstanding. This compares with a net loss of $140.9 million or $1.36 per share based on 103.7 million fully diluted weighted average shares outstanding for 2021. Revenue for fiscal '22 was $243.2 million compared to $138.3 million for 2021.

謝謝你，詹姆斯，大家下午好。正如我們今天報導的那樣，我們 2022 財年的淨虧損為 1.761 億美元或每股 1.67 美元，基於 1.054 億股完全稀釋的加權平均流通股。相比之下，根據 2021 年 1.037 億股完全稀釋的加權平均流通股，淨虧損為 1.409 億美元或每股 1.36 美元。'22 財年的收入為 2.432 億美元，而 2021 年為 1.383 億美元。

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 includes managing the ongoing AAT Phase II clinical trials for Takeda and delivering a Phase I ready candidate to Horizon. There remains $128.4 million of revenue to be recognized associated with the Takeda collaboration, which we anticipate will be recognized over the next 2 to 3 years.

本期收入主要與我們與武田和地平線的合作協議有關。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。與武田合作相關的收入仍有 1.284 億美元待確認，我們預計這將在未來 2 至 3 年內確認。

And there remains $66.7 million of revenue to be recognized for Horizon, which we anticipate will be recognized.

Horizon 仍有 6670 萬美元的收入需要確認，我們預計這將得到確認。

(technical difficulty)

（技術難度）

And please remain on the line. Your conference will resume shortly.

請保持在線。您的會議將很快恢復。

Sorry, folks, we had a connection problem there. I'll continue about halfway through our -- my prepared remarks. Net cash used by operating activities during fiscal 2022 was $136.1 million compared with net cash provided by operating activities of $171.2 million during 2021. The increase in cash used by operating activities is driven primarily by research and development expenses. We expect our operating cash burn to be $70 million to $90 million per quarter in fiscal 2023, and we expect capital expenditures up to $200 million as we near completion on our footprint expansion projects, including GMP manufacturing.

抱歉，伙計們，我們在那裡遇到了連接問題。我將繼續講到一半——我準備好的發言。 2022 財年經營活動使用的現金淨額為 1.361 億美元，而 2021 財年經營活動提供的現金淨額為 1.712 億美元。經營活動使用的現金增加主要是由研發費用推動的。我們預計 2023 財年每季度的運營現金消耗將達到 7000 萬至 9000 萬美元，隨著我們即將完成包括 GMP 製造在內的足跡擴張項目，我們預計資本支出將高達 2 億美元。

Turning to our balance sheet. Our cash and investments totaled $482.3 million at September 30, 2022, compared with $613.4 million at September 30, 2021. The decrease in our cash and investments was primarily due to cash used for operating activities. Our common shares outstanding at September 30, 2022, were 106.0 million.

轉向我們的資產負債表。截至 2022 年 9 月 30 日，我們的現金和投資總額為 4.823 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。截至 2022 年 9 月 30 日，我們的已發行普通股為 1.06 億股。

As Chris mentioned earlier, on November 9, in 2022, the company and Royalty Pharma entered into a Royalty Purchase Agreement pursuant to which Royalty Pharma agreed to pay up to $410 million in cash to the company in consideration for the company's future royalty interest in olpasiran, originally developed by the company and out licensed to Amgen, in 2016.

正如 Chris 之前提到的，2022 年 11 月 9 日，公司與 Royalty Pharma 簽訂了特許權使用費購買協議，根據該協議，Royalty Pharma 同意向公司支付高達 4.1 億美元的現金，作為公司未來在 olpasiran 的特許權使用費權益，最初由該公司開發，並於 2016 年授權給 Amgen。

Pursuant to the Royalty Pharma agreement, Royalty Pharma paid $250 million upfront and agreed to pay an additional -- up to an additional $160 million contingent upon the achievement of certain clinical, regulatory and sales milestones.

根據與 Royalty Pharma 的協議，Royalty Pharma 預先支付了 2.5 億美元，並同意支付額外的費用——最多額外支付 1.6 億美元，具體取決於某些臨床、監管和銷售里程碑的實現。

The company retained rights to $400 million in development, regulatory and sales milestones payments, potentially due from Amgen from the same 2016 out-licensing agreement. Pro forma cash and investments at September 30, 2022, including the Royalty Pharma cash received would be $732.3 million. I will now turn the call back to Chris.

該公司保留了 4 億美元的開發、監管和銷售里程碑付款的權利，這可能是安進根據 2016 年同一份許可協議支付的。截至 2022 年 9 月 30 日的備考現金和投資，包括收到的 Royalty Pharma 現金，將為 7.323 億美元。我現在將電話轉回給克里斯。

Thanks, Ken. In our business opportunity abounds. There is no shortage of need that the biopharmaceutical industry can endeavor to serve and no shortage of lives that can be touched. There's also no shortage of risk as unknowns abound. As such, clarity is at a premium and will often be a primary value driver. We feel good about the clarity we have recently achieved and expect to achieve in the short term. These include the following: planning for fazirsiran's Phase III is complete, and currently under review with the FDA and SEQUOIA data are in. We expect to be able to give guidance on the Phase III and present top line SEQUOIA data with Takeda shortly.

謝謝，肯。在我們這裡商機比比皆是。不缺少生物醫藥產業可以竭力服務的需求，不缺少可以觸及的生命。由於未知數比比皆是，因此也不乏風險。因此，清晰度非常重要，而且通常是主要的價值驅動因素。我們對最近實現並期望在短期內實現的清晰度感到滿意。其中包括：fazirsiran 的 III 期計劃已經完成，目前正在接受 FDA 的審查，並且 SEQUOIA 數據已在。我們希望能夠很快就 III 期提供指導，並與武田一起提供頂級 SEQUOIA 數據。

Interim Phase II data from ARO-ANG3 and ARO-APOC3 suggests that both drug candidates are doing what they are designed to do, and we have good plans as to how to apply these in various patient populations. We expect multiple end of Phase II meetings in 2023 and to initiate multiple Phase III studies shortly thereafter. Progress with ARO-MUC5AC and ARO-RAGE in Phase I/II studies has been good. We expect interim data that could provide clinical proof of concept in the first half of 2023.

來自 ARO-ANG3 和 ARO-APOC3 的中期 II 期數據表明，這兩種候選藥物都在做它們設計要做的事情，我們有很好的計劃如何將它們應用於不同的患者群體。我們預計 2023 年將多次結束 II 期會議，並在此後不久啟動多項 III 期研究。 ARO-MUC5AC 和 ARO-RAGE 在 I/II 期研究中的進展一直很好。我們預計中期數據可以在 2023 年上半年提供概念的臨床證明。

ARO-C3 is progressing well in a Phase I/II study, and we expect interim data that could provide proof of concept in the first half of 2023. Our discovery engine continues to perform, and we expect to announce the next cell type we will be targeting in the first half of 2023. We have provided better clarity with respect to our balance sheet with our sale of olpasiran royalty rights for $250 million upfront plus $160 million potential additional payments. This is on top of the remaining $400 million we could access in clinical, regulatory and sales milestone payments from Amgen.

ARO-C3 在 I/II 期研究中進展順利，我們預計中期數據可以在 2023 年上半年提供概念證明。我們的發現引擎將繼續發揮作用，我們預計將宣布下一個細胞類型目標是在 2023 年上半年。我們以 2.5 億美元的預付款加上 1.6 億美元的潛在額外付款出售了 olpasiran 特許權使用費，從而使我們的資產負債表更加清晰。這是我們可以從 Amgen 獲得的剩餘 4 億美元的臨床、監管和銷售里程碑付款的基礎。

And finally, we have announced our 20 in '25 campaign. Our plan of having 20 individual drugs in clinical trials or ad market in 2025 will be a remarkable accomplishment that we believe will represent a large leap forward for medicine and position Arrowhead as a truly unique and impactful biopharmaceutical company. Thank you for joining us today. And I would now like to turn the call over to questions. Operator?

最後，我們宣布了 20 in '25 活動。我們計劃在 2025 年有 20 種藥物進入臨床試驗或廣告市場，這將是一項了不起的成就，我們相信這將代表醫學的巨大飛躍，並將 Arrowhead 定位為一家真正獨特且有影響力的生物製藥公司。感謝您今天加入我們。我現在想將電話轉為問題。操作員？

(Operator Instructions). And our first question comes from Maury Raycroft from Jefferies.

（操作員說明）。我們的第一個問題來自 Jefferies 的 Maury Raycroft。

Just going to ask one on AAT. Wondering if you can clarify if you or Takeda has shared the Phase II biopsy data with FDA? And if their feedback will be based on the biopsy data or only the serum biomarker knockdown data?

只是想問一個關於 AAT 的問題。想知道您是否可以澄清您或武田是否與 FDA 共享了 II 期活檢數據？他們的反饋是基於活檢數據還是僅基於血清生物標誌物敲低數據？

Javier?

哈維爾？

Yes, the feedback that we're looking is at the Phase III protocol design that was already discussed twice. And as Chris said, we already -- Takeda already incorporated most of the feedback. So this is more a procedure than anything else. And the SEQUOIA data is not part of this feedback that we're looking for. In other way, the SEQUOIA data that was necessary to inform the Phase III was already presented and is part of the discussion that we having with the agency over the last 4 or 5 months.

是的，我們正在尋找的反饋是關於已經討論過兩次的第三階段協議設計。正如克里斯所說，我們已經——武田已經採納了大部分反饋。所以這更像是一個程序。並且 SEQUOIA 數據不是我們正在尋找的反饋的一部分。換句話說，通知 III 階段所需的 SEQUOIA 數據已經提交，並且是我們在過去 4 或 5 個月內與該機構進行的討論的一部分。

Got it. Okay. Okay. And then for the AAT data that you have in hand, can you comment on what you're seeing and better set expectations for what you will disclose? And if you start the Phase III in the first quarter of next year, do you think the update will happen in December or more likely around JPMorgan meeting in early January?

知道了。好的。好的。然後對於您手頭的 AAT 數據，您能否評論您所看到的並更好地設定對您將披露的內容的期望？如果你在明年第一季度開始第三階段，你認為更新會在 12 月發生，還是更有可能在 1 月初的摩根大通會議前後發生？

Yes. I can't give too granular guidance on the timing for the update. But I'll tell you, my hope is that we can do that in December. We just have to see what schedules look like. We expect the feedback, if any, from FDA almost any day now. And so we do have time to get that in December. And so we'll see. With respect to giving further guidance on the SEQUOIA data, we're just not going to do that. We will provide that update at the same time as we give guidance on what the Phase III will look like.

是的。我無法就更新時間提供過於細化的指導。但我會告訴你，我希望我們能在 12 月做到這一點。我們只需要看看時間表是什麼樣的。我們幾乎每天都期待 FDA 的反饋（如果有的話）。所以我們確實有時間在 12 月獲得它。所以我們拭目以待。關於對 SEQUOIA 數據提供進一步指導，我們只是不打算那樣做。我們將在就第三階段的情況提供指導的同時提供該更新。

And our next question comes from Luca Issi from RBC Capital.

我們的下一個問題來自 RBC Capital 的 Luca Issi。

I have a quick one on APO versus ANG. It looks to me that you're prioritizing APOC3 over ANG3, especially for the larger mixed dyslipidemia population, can you expand a little bit more on the rationale behind the decision? And is it fair to assume that you're looking for a partner for APOC3 given that you need to run a cardiovascular outcome trial?

我有一個關於 APO 與 ANG 的快速對比。在我看來，您將 APOC3 置於 ANG3 之上，尤其是對於較大的混合性血脂異常人群，您能否進一步闡述該決定背後的理由？鑑於您需要進行心血管結果試驗，假設您正在為 APOC3 尋找合作夥伴是否公平？

I'll take the second part, and then I'll hand the first part over to Javier. The answer is no, we are not looking for a partner for APOC3. That, to us, feels like an important opportunity for us. The data have been, from our perspective, unequivocal. And we see a large opportunity in large markets as well as smaller SHTG market and then, of course, the very small FCS market. So we like the opportunity, and we intend to conduct that cardiovascular outcome study ourselves and to commercialize that drug ourselves.

我將負責第二部分，然後我會將第一部分交給 Javier。答案是否定的，我們不是在為 APOC3 尋找合作夥伴。對我們來說，這對我們來說是一個重要的機會。從我們的角度來看，這些數據是明確的。我們在大型市場以及較小的 SHTG 市場，當然還有非常小的 FCS 市場中看到了巨大的機會。所以我們喜歡這個機會，我們打算自己進行心血管結果研究，並自己將這種藥物商業化。

Yes. So a couple of things. So first, the Phase II data or the interim data that we presented at the American Heart Association really confirmed what we learned in the Phase I/II studies. So it wasn't about prioritization. It was about to really learn and confirm the specific therapeutic effect of these 2 molecules. And as we said before, ANG seems to be a drug that is more focused on hypercholesterolemia, and that is how we see the opportunity.

是的。所以有幾件事。因此，首先，我們在美國心臟協會提交的 II 期數據或中期數據確實證實了我們在 I/II 期研究中學到的知識。所以這與優先順序無關。即將真正了解並確認這2個分子的具體治療效果。正如我們之前所說，ANG 似乎是一種更專注於高膽固醇血症的藥物，這就是我們看到機會的方式。

Now that's a much crowded space, when you think about the general hypercholesterolemia population, but this drug has a very unique pathway and mechanism of action that can address these specific smaller population the rare HoFH and the not so rare HeFH. So it's not about prioritization, but it's about where the profile of this drug fit in the context of clinical care particularly when you fast forward a few years from now. So ARO-APOC3, as you saw the data that we knew about the severe hypertriglyceridemia populations is confirmed, and it's very remarkable and is consistent.

現在這是一個非常擁擠的空間，當你考慮一般的高膽固醇血症人群時，但這種藥物具有非常獨特的途徑和作用機制，可以解決這些特定的較小人群，即罕見的 HoFH 和不太罕見的 HeFH。所以這與優先次序無關，而是關於這種藥物在臨床護理環境中的位置，特別是當你從現在快進幾年時。所以 ARO-APOC3，正如你所看到的，我們所知道的關於嚴重高甘油三酯血症人群的數據得到了證實，它非常顯著並且是一致的。

And as I always said, with these therapeutics, we have 100% response with regard to hypertriglyceridemia. So our initial plan to go with the 2 severe hypertriglyceridemia syndrome, the FCS or the SHTG continue to be the same. What we are learning, and I think that was a key feature of our Analyst and Investor Day is what is the unmet medical need in cardiovascular risk reduction in the next 5 to 10 years. And we believe that the LDL cholesterol issue is probably well taken care of and the rest of the risks come from different sources of lipid and lipoprotein most of which are addressed with the ARO-APOC3 molecule. So in conclusion, we see the opportunity where the unmet medical need is and ARO-APOC3 fit very well those criteria. So it's not about prioritization, but it's really going to where the drugs have the biggest promise.

正如我常說的，通過這些療法，我們對高甘油三酯血症有 100% 的反應。因此，我們最初的計劃與 2 種嚴重的高甘油三酯血症綜合徵、FCS 或 SHTG 一起使用。我們正在學習的，我認為這是我們的分析師和投資者日的一個關鍵特徵是，未來 5 到 10 年在降低心血管風險方面未滿足的醫療需求是什麼。我們相信低密度脂蛋白膽固醇問題可能已得到很好的解決，其餘風險來自不同來源的脂質和脂蛋白，其中大部分由 ARO-APOC3 分子解決。因此，總而言之，我們看到了未滿足醫療需求的機會，而 ARO-APOC3 非常符合這些標準。所以這與優先次序無關，但它確實會用於藥物最有希望的地方。

Yes. Look, I think that our development programs worked exactly as we design them to work. We have these 2 drug candidates that were clearly active and clearly had some overlap in their activity. And people would ask how we're going to apply these 2 drugs to various patient populations. And our answer always was we need to look at the data, and that will guide us. That was not a satisfactory answer to some people, but that was the answer.

是的。聽著，我認為我們的開發計劃完全按照我們設計的那樣運作。我們有這 2 種候選藥物，它們顯然很活躍，而且它們的活性顯然有一些重疊。人們會問我們如何將這兩種藥物應用於不同的患者群體。我們的答案始終是我們需要查看數據，這將指導我們。對某些人來說，這不是一個令人滿意的答案，但這就是答案。

And now that we have an interim look, we've got a better idea about how these will help various patient populations. And so now I think we've got a good idea. Again, as Javier said, we don't view this as prioritizing. We view this as just following where these drugs are going to have their greatest benefit in which patients.

現在我們有了初步的了解，我們對這些將如何幫助不同的患者群體有了更好的了解。所以現在我認為我們有了一個好主意。同樣，正如 Javier 所說，我們不認為這是優先事項。我們認為這只是在追踪這些藥物將在哪些患者身上獲得最大益處。

And our next question comes from Ellie Merle from UBS.

我們的下一個問題來自瑞銀的 Ellie Merle。

For the initial pulmonary readout in the first half of next year, I guess what are you looking to see in terms of the degree of protein knockdown based on the dose levels that you're studying in healthy volunteers? And I guess when you think about pulmonary delivery, I guess, what does proof of concept for the pulmonary platform look like from this readout or if perhaps we need to wait for longer-term data?

對於明年上半年的初始肺部讀數，我想您希望根據您在健康志願者中研究的劑量水平，從蛋白質敲低的程度來看看到什麼？我想當你考慮肺部輸送時，我想，從這個讀數來看，肺部平台的概念證明是什麼樣的，或者我們是否需要等待更長期的數據？

Sure. Look, I think these are well-validated targets, particularly MUC5AC. But I think even RAGE and certainly MMP7. And so our thinking is that if we can see a well-tolerated deep knockdown in healthy volunteers, that is a substantial clinical proof of concept. We will also have some data later in the year in various patient populations. But I think if we can see good consistent knockdown in healthy volunteers that's well tolerated, I think that is giant leap forward for the entire platform and certainly for the individual candidates. With respect to how much knockdown we need, I don't think we're setting expectations for ourselves here. I think we want to see what we see. But our hope is that we see consistent and at least relatively deep knockdown. And if we can, I think that given the importance of these targets, I think that they will have disease-modifying effects.

當然。看，我認為這些是經過充分驗證的目標，尤其是 MUC5AC。但我認為甚至是 RAGE，當然還有 MMP7。因此我們的想法是，如果我們能在健康志願者中看到耐受性良好的深度擊倒，那將是一個重要的臨床概念證明。我們還將在今年晚些時候在不同的患者群體中獲得一些數據。但我認為，如果我們能夠在耐受性良好的健康志願者中看到良好的持續擊倒，我認為這對整個平台來說都是巨大的飛躍，當然對個人候選人來說也是如此。關於我們需要多少擊倒，我不認為我們在這里為自己設定期望。我想我們想看到我們所看到的。但我們希望看到一致且至少相對較深的擊倒。如果可以的話，我認為鑑於這些目標的重要性，我認為它們將具有緩解疾病的作用。

And our next question comes from Joel Beatty from Baird.

我們的下一個問題來自 Baird 的 Joel Beatty。

For the lung programs, MUC5AC and RAGE, I think in your prepared remarks you mentioned that both of these programs are going to be reaching the top of the -- on the SAD cohorts and also showing MAD cohorts. How do you decide the peak dosing of those? Is this kind of preset? Or are you looking at safety or efficacy markers?

對於肺部項目 MUC5AC 和 RAGE，我想在您準備好的發言中提到，這兩個項目都將在 SAD 隊列中名列前茅，並且還會顯示 MAD 隊列。你如何決定這些藥物的峰值劑量？是這種預設嗎？或者您正在查看安全性或療效標記？

So the dose levels for the SAD and MAD are largely preset. And then as we go from one dose level to the next, we have an independent Data Safety Committee that reviews aggregate safety data and votes to allow dose escalation from the dose just completed to the next higher dose. Hopefully, that addresses your question.

因此，SAD 和 MAD 的劑量水平在很大程度上是預設的。然後，當我們從一個劑量水平轉到下一個劑量水平時，我們有一個獨立的數據安全委員會，負責審查匯總的安全數據並投票，以允許從剛剛完成的劑量升級到下一個更高劑量。希望這能解決您的問題。

Great. And then for the cardio drugs APOC3 and ANG3, do you see the market opportunity as more of displacing current drugs and being used in place of them or as add-on therapies to the current set of drugs in the market?

偉大的。然後對於心臟藥物 APOC3 和 ANG3，您是否認為市場機會更多是取代現有藥物並替代它們或作為市場上現有藥物集的附加療法？

I think it's a little bit too early to opine on that. That's a broad question. Give us some more time so we can complete the Phase II, and we have a better idea about what that looks like and we can go from there. But at this point, I don't think that we want to get into how we slot into various therapeutic paradigms.

我認為現在就此發表意見還為時過早。這是一個廣泛的問題。給我們更多時間，以便我們可以完成第二階段，我們對它的外觀有更好的了解，我們可以從那裡開始。但在這一點上，我認為我們不想深入了解我們如何融入各種治療範式。

And our next question comes from Edward Tenthoff from Piper Sandler.

我們的下一個問題來自 Piper Sandler 的 Edward Tenthoff。

Two questions, if I may. Just housekeeping, what was the fourth quarter weighted average shares outstanding, if you have them to 3 decimal points? But then for Chris, kind of high level question. You guys have been so successful at partnering different therapies. You've been clear that cardiovascular is a key area of focus. How are you really looking at the pipeline going forward? Is pulmonary disease going to be an area of -- or a second area of focus? Are you going to look to partner some of those therapies? How should we be thinking about where you guys are going to stay focused and specialized?

兩個問題，如果可以的話。只是整理一下，第四季度加權平均流通股數是多少，如果你有小數點後三位？但對克里斯來說，這是一個高層次的問題。你們在合作不同的療法方面非常成功。您已經清楚心血管是重點關注的領域。您如何真正看待未來的管道？肺部疾病會成為關注的一個領域還是第二個關注領域？您打算與其中一些療法合作嗎？我們應該如何考慮你們將在哪裡保持專注和專業？

Sure. Ken, do you want to address the first question?

當然。 Ken，你想回答第一個問題嗎？

Yes. The weighted average shares for Q4 were 105. 879 million.

是的。第 4 季度的加權平均股數為 105. 8.79 億股。

Awesome. And then again, just in terms of higher level, obviously, a focus on cardiovascular disease. What else are you guys thinking about partnering or what is going to be core?

驚人的。再一次，就更高層次而言，顯然是對心血管疾病的關注。你們還有什麼關於合作的想法，或者什麼是核心？

Sure. Thanks, Ed. So broadly, of course, that's a dynamic question because as the company grows and as market appetite's for various targets and drugs change, of course, that which can be partnered changes. Having said all of that, look, as we've said in the past, we like cardiovascular. We like what we're seeing with APOC3 and ANG3. We like the idea of building commercial force to address those. We like the staged approach there starting with HoFH and expanding into HeFH.

當然。謝謝，埃德。如此廣泛，當然，這是一個動態的問題，因為隨著公司的發展以及市場對各種目標和藥物的需求發生變化，當然，可以合作的對像也會發生變化。說了這麼多，看，就像我們過去說過的，我們喜歡心血管。我們喜歡我們所看到的 APOC3 和 ANG3。我們喜歡建立商業力量來解決這些問題的想法。我們喜歡從 HoFH 開始並擴展到 HeFH 的分階段方法。

We like the idea of starting with small FCS and expanding into SHTG and expanding into mixed dyslipidemia. Now with regard to the pulmonary, look, that's a very interesting area. We think that's a target-rich environment. That feels to us like another liver. And we think, look, we can address that market. I think there are 16,000-or-so pulmonologists in the U.S., and we see not 2 or 3 or 4 drugs, but 8 or 9 or 10 drugs. So I think that we will play there.

我們喜歡從小型 FCS 開始擴展到 SHTG 並擴展到混合性血脂異常的想法。現在關於肺部，看，這是一個非常有趣的領域。我們認為這是一個目標豐富的環境。這對我們來說就像另一個肝臟。我們認為，看，我們可以解決這個市場。我認為美國有大約 16,000 名肺科醫生，我們看到的不是 2、3 或 4 種藥物，而是 8、9 或 10 種藥物。所以我認為我們會在那裡玩。

Now because it's so target rich, I think we also could do some partnerships there at some point. We're not looking to partner these first 3 right now. But I think there's room there for us to build a real franchise. And then also to work with the right companies on a handful of other targets potentially. And then you look at our other candidates, C3, that's a very interesting drug candidate to hold on to ourselves. That gives us an awful lot of optionality in terms of how we commercialize that, where we go, how fast we can get there. So anyway, that's sort of a broad answer to your question, I guess.

現在因為它的目標如此豐富，我認為我們也可以在某個時候在那裡建立一些合作夥伴關係。我們現在不打算與前 3 家合作。但我認為我們有空間建立一個真正的特許經營權。然後還可能與合適的公司就其他幾個目標進行合作。然後你看看我們的其他候選人，C3，這是一個非常有趣的候選藥物，可以讓我們堅持下去。在我們如何將其商業化、我們去哪裡、我們能多快到達那裡方面，這給了我們很多選擇權。所以無論如何，我想這是對你的問題的廣泛回答。

And just hats off on the Royalty financing. That's a great deal.

並且對版稅融資表示敬意。這很重要。

Thank you.

謝謝你。

And our next question comes from Patrick Trucchio from H.C. Wainwright.

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

I'm just wondering, I have a follow-up just on the platform. And if you can discuss the relative advantages of the siRNA approach as it compares to others such as small molecules or gene editing, specifically in the area of alpha-1. So also more broadly across the pipeline, what is your level of confidence that siRNA will be the preferred mechanism in these various targets and indications and the programs currently underway, particularly as these other modalities advance in clinical development?

我只是想知道，我在平台上有後續行動。如果您可以討論 siRNA 方法與其他方法（例如小分子或基因編輯）相比的相對優勢，特別是在 alpha-1 領域。因此，在更廣泛的管道中，您對 siRNA 將成為這些不同目標和適應症以及目前正在進行的項目的首選機制的信心程度如何，特別是隨著這些其他方式在臨床開發中的進步？

Sure. So look, that's a little bit of a hard question to answer broadly because various drug candidates will have specific advantage. But I'll tell you broadly the way we look at this. RNAi is not the right modality for every indication, of course, but for many indications where you need to reduce the expression of some gene product, it's a good one. I think we've shown -- we and others have shown time and time again that RNAi appears to be a potentially better modality than antisense oligos in terms of dosing schedule, in terms of depth of knockdown, in terms of safety.

當然。所以看，這是一個很難廣泛回答的問題，因為各種候選藥物都有特定的優勢。但我會大致告訴你我們看待這個問題的方式。當然，RNAi 並非適用於所有適應症，但對於許多需要減少某些基因產物表達的適應症，它是一種很好的方法。我認為我們已經證明——我們和其他人已經一次又一次地表明，就給藥方案、擊倒深度和安全性而言，RNAi 似乎是一種可能比反義寡核苷酸更好的方式。

We think that will continue, at least as it relates to hepatocyte targets, and we'll see if that applies more broadly. When you look at gene editing, look, I think that's an interesting idea. I think that we're not quite ready for prime time there. And I think that there is a permanence associated with gene editing that may be -- that may cause some pause with -- at least for certain indications.

我們認為這將繼續下去，至少與肝細胞靶點相關，我們將看看這是否適用於更廣泛的領域。當你看基因編輯時，看，我認為這是一個有趣的想法。我認為我們還沒有準備好迎接那裡的黃金時段。我認為與基因編輯相關的持久性可能是——這可能會導致一些停頓——至少在某些情況下是這樣。

What's great about RNAi is that we get a good, long, durable effect, but yet it is ultimately reversible. After some period of time, that drug wears off. And it doesn't knock down the gene product any longer. What would concern me at least in the near to midterm with the gene editing approach is that the idea of having to unCRISPRize something is a daunting one. And so I think it's still a bit of an early technology. But at least as it relates to the indications we're going after, we believe that RNAi at least in our current pipeline is likely to -- and from my perspective, at least the preferred modality.

RNAi 的偉大之處在於我們獲得了良好、持久、持久的效果，但它最終是可逆的。一段時間後，該藥物會消失。而且它不再擊倒基因產物。至少在近期和中期，基因編輯方法會讓我擔心的是，必須對某些東西進行 unCRISPRize 的想法是一個令人生畏的想法。所以我認為它仍然是一項早期技術。但至少因為它與我們正在追求的跡像有關，我們相信 RNAi 至少在我們目前的管道中很可能——從我的角度來看，至少是首選的方式。

Yes. That's helpful. And then earlier in the call, there was commentary around increased clarity on which programs and how large the pipeline could become in the next few years with the goals outlined through 2025. So I'm wondering if you can elaborate a bit more on this commentary, particularly regarding gating factors involved in deciding which targets or disease to pursue, such as the level of genetic or clinical validation required? And how many programs either in terms of new INDs or some other metric would you be expected to announce on an annual basis going forward as you expand the pipeline?

是的。這很有幫助。然後在電話會議的早些時候，有人評論說，隨著 2025 年之前概述的目標，未來幾年哪些項目和管道規模會變得更加清晰。所以我想知道你是否可以對此評論進行更多闡述，特別是關於決定追求哪些目標或疾病的門控因素，例如所需的遺傳或臨床驗證水平？隨著您擴大管道，您預計每年會宣布多少新 IND 或其他指標的項目？

Well, yes. So we're excited about our 20 in '25 program. We feel comfortable that we'll get there. I think 20 clinical candidates, whether wholly owned or partnered is a lofty goal, and I think we're going to achieve it. Regarding genetically validated targets and such, if you go down our pipeline, I think that there is pretty good consensus that these are all well-validated targets. With the possible exception of HBV just because it's a complicated virus, of course.

嗯，是。所以我們對我們的 20 in '25 計劃感到興奮。我們感到很自在，我們會到達那裡。我認為 20 名臨床候選人，無論是獨資還是合作，都是一個崇高的目標，我認為我們將實現這一目標。關於經過基因驗證的目標等，如果你沿著我們的管道走下去，我認為人們已經達成了很好的共識，即這些都是經過充分驗證的目標。當然，HBV 可能是個例外，因為它是一種複雜的病毒。

But everything else, I think, clearly, there is consensus among KOLs that if you can reduce the expression of these various targets, positive phenotypes will result. And our goal is to continue with that. Second, if you look down our pipeline, everything we've gone after, we've been the first RNAi player there. I'd like to continue that. At least in the near term, I think we will be continuing that. And then finally, with respect to our ability to get outside the liver. As we talked about with pulmonary, with skeletal muscle, we'll be announcing our next cell type in the first half of next year.

但我認為，顯然，KOL 之間存在其他一切，如果你能減少這些不同目標的表達，就會產生積極的表型。我們的目標是繼續這樣做。其次，如果你看看我們的管道，我們所追求的一切，我們一直是那裡的第一個 RNAi 播放器。我想繼續這樣。至少在短期內，我認為我們會繼續這樣做。最後，關於我們離開肝臟的能力。正如我們談到肺和骨骼肌一樣，我們將在明年上半年宣布我們的下一種細胞類型。

With all of these, it gives us the ability to run out and take land, right? We don't see any near-term competitors in these extra hepatic spaces at least so far, and so it gives us the ability to really be choosy and go after targets that are well validated to decrease our biology risk.

有了所有這些，它就給了我們跑出去奪取土地的能力，對吧？至少到目前為止，我們在這些額外的肝臟空間中沒有看到任何近期競爭對手，因此它使我們能夠真正挑剔並追求經過充分驗證的目標，以降低我們的生物學風險。

And our next question comes from Madhu Kumar from Goldman Sachs.

我們的下一個問題來自高盛的 Madhu Kumar。

Maybe following up on Ellie's question, what do you think is the dynamic range of RAGE and MUC5AC knockdown that will be predictive of clinical benefit in these obstructive pulmonary conditions?

也許跟進 Ellie 的問題，您認為 RAGE 和 MUC5AC 敲低的動態範圍是多少，可以預測這些阻塞性肺病的臨床益處？

James?

詹姆士？

Yes. So for RAGE, I would say, based on our animal data, we were in the Alternaria area model that we presented at ATS, we were wanting to get better than 50% knockdown -- 60% to 70% knockdown in that particular animal model. And then for MUC5AC, I think if you look at the patient data versus the healthy volunteer expression level for MUC5AC that patients have maybe tenfold more MUC5AC compared to what the [healthy] has. So I think that -- and you probably don't have to bring the patients back to normal levels to have a benefit. But particularly in the patients, I think there's pretty significant dynamic range in terms of MUC5AC knockdown such that if you get 50% reduction in MUC5AC expression, we may see an associated clinical benefit. I don't know if that addresses your question.

是的。所以對於 RAGE，我想說，根據我們的動物數據，我們在 ATS 展示的鍊格孢屬區域模型中，我們希望在該特定動物模型中獲得超過 50% 的擊倒率——60% 到 70% 的擊倒率.然後對於 MUC5AC，我認為如果您查看患者數據與 MUC5AC 的健康志願者表達水平，那麼與 [健康] 相比，患者的 MUC5AC 可能多十倍。所以我認為——你可能不必讓患者恢復到正常水平就能獲益。但特別是在患者中，我認為在 MUC5AC 敲低方面存在相當大的動態範圍，因此如果 MUC5AC 表達減少 50%，我們可能會看到相關的臨床益處。我不知道這是否解決了你的問題。

No, that's helpful. Maybe on AAT, I guess kind of -- how much different would you expect the SEQUOIA data to be from the Phase II open-label extension given kind of patient recruitment in SEQUOIA relative to the open-label extension? Is there any reasons for it to be a significant difference in the disease course in the SEQUOIA patients relative to the open label extension?

不，那很有幫助。也許在 AAT 上，我猜有點——鑑於 SEQUOIA 中相對於開放標籤擴展的患者招募類型，您希望 SEQUOIA 數據與第二階段開放標籤擴展有多大不同？與開放標籤擴展相比，SEQUOIA 患者的病程是否存在顯著差異？

I don't believe so. No, they should be similar. Look, we always viewed that open-label data as important in terms of pegging a story. It was a small number of patients, but we thought it pegged the story. And we have been looking for -- we've been hoping that SEQUOIA would confirm that story.

我不這麼認為。不，它們應該是相似的。看，我們一直認為開放標籤數據在追踪故事方面很重要。這是一小部分患者，但我們認為它與故事掛鉤。我們一直在尋找——我們一直希望紅杉能夠證實這個故事。

And our next question comes from Mayank Mamtani from B. Riley.

我們的下一個問題來自 B. Riley 的 Mayank Mamtani。

I appreciate you putting out the 2025 campaign. So maybe on the SHASTA study, a quick follow-up on the 2 pancreatic events that you saw there admittedly in a blinded manner, but is that what you would expect for a study this size? And in general, what would be the event rate for SHTG study? And maybe a second part, as you think about validating triglyceride as an approvable end point for either SHTG or for larger mixed dyslipidemia indication, how are you sort of thinking about that next year?

感謝您開展 2025 年競選活動。因此，也許在 SHASTA 研究中，對您在那里以盲法方式看到的 2 個胰腺事件進行快速跟進，但這是您對這種規模的研究的期望嗎？一般來說，SHTG 研究的事件發生率是多少？也許是第二部分，當你考慮將甘油三酯作為 SHTG 或更大的混合性血脂異常適應症的可批准終點時，你對明年有什麼看法？

Yes. So with regards to the 2 cases of pancreatitis are well within the expected event rate, which is about 3% to 5% per year in this patient population. So we saw 2 cases in about 200 patients and by the time we -- I mean, by now we have almost 1 year follow-up in most of those patients. So yes, the event rate is what we expected. And the second part with regard to the Phase III study, I think we commented on this before, the registration program for ARO-APOC3 in the severe hypertriglyceridemia indication does not need pancreatitis endpoint for approval.

是的。因此，關於 2 例胰腺炎，完全在預期的事件發生率之內，在該患者群體中，事件發生率約為每年 3% 至 5%。所以我們在大約 200 名患者中看到了 2 個病例，到那時我們——我的意思是，到目前為止，我們對大多數患者進行了將近 1 年的隨訪。所以是的，事件發生率是我們預期的。第二部分關於III期研究，我想我們之前已經評論過，ARO-APOC3在嚴重高甘油三酯血症適應症中的註冊程序不需要胰腺炎終點的批准。

But of course, we would like to enrich the patient population as much as possible to provide information about pancreatitis risk reduction, which is the goal of therapy. And that would be very important for many other reasons really to translate the clinical benefit, to define the value proposition and so forth. So the approval path does not require pancreatitis, we will do our best to have enough number of patients at high risk. So we can see the risk reduction in pancreatitis as a consequence of normalizing triglyceride levels.

但當然，我們希望盡可能豐富患者群體，以提供有關降低胰腺炎風險的信息，這是治療的目標。由於許多其他原因，這對於真正轉化臨床益處、定義價值主張等非常重要。所以批准路徑不需要胰腺炎，我們會盡最大努力有足夠數量的高風險患者。因此，我們可以看到甘油三酯水平正常化後胰腺炎的風險降低。

And then just a quick one on A1AT. Are you able to comment on how -- as you think about Phase III, how are you thinking about placebo response? Because there have been studies recently put out independent of this program and also by Takeda about how to sort of think about F2, F3 patients differently. So is there anything you could comment on that on the placebo response for Phase III, how you might be thinking about?

然後只是關於 A1AT 的快速介紹。你能評論一下——當你考慮第三階段時，你是如何考慮安慰劑反應的？因為最近有獨立於該計劃的研究以及武田關於如何以不同方式思考 F2、F3 患者的研究。那麼對於第三階段的安慰劑反應，您有什麼可以評論的嗎？您可能會怎麼想？

So we're going to use the totality of the data available to estimate the placebo rate and that would be part of the equation for the effect, size and the power for the study. So you will see that in detail whenever we can do this event with Takeda and present the SEQUOIA data and the Phase III study design. So we, of course, use the totality of the data to plan for that study.

因此，我們將使用全部可用數據來估計安慰劑率，這將成為研究效果、規模和功效等式的一部分。因此，無論何時我們可以與 Takeda 進行此活動並展示 SEQUOIA 數據和 III 期研究設計，您都會詳細了解這一點。因此，我們當然會使用全部數據來計劃該研究。

And our next question comes from Keay Nakae from Chardan.

我們的下一個問題來自 Chardan 的 Keay Nakae。

Chris, one question on AATD, the Phase III design, is it your expectation that the agency will or will not require care biopsy data?

克里斯，關於 AATD 的一個問題，即 III 期設計，您是否期望該機構需要或不需要護理活檢數據？

Yes. So the biopsy data is likely to be the key endpoint. That's where we will -- we're thinking that's what we studied. That's what the disease is defined by. So this is a disease about fibrosis progression and end-stage liver disease so cirrhosis. So the goal of therapy is to prevent fibrosis progression or to reduce fibrosis severity. So that seems to me a logical approvable endpoint in a condition that is defined by fibrosis progression.

是的。所以活檢數據很可能是關鍵終點。這就是我們要做的——我們認為這就是我們研究的內容。這就是疾病的定義。所以這是一種關於纖維化進展和終末期肝病的疾病，即肝硬化。因此，治療的目標是防止纖維化進展或降低纖維化的嚴重程度。因此，在我看來，在由纖維化進展定義的情況下，這似乎是一個合乎邏輯的可批准終點。

And our next question comes from Mani Foroohar from SVB.

我們的下一個問題來自 SVB 的 Mani Foroohar。

I've got a couple of questions more about your own sort of rationale and strategy given that a lot of other analysts have dug into the details of this or that specific program. So I'll start with SEQUOIA. Did I hear right that your plan is to disclose the upcoming SEQUOIA data green biopsy alongside the Phase III trial design? And if so, could you give me a sense of the rationale of why those 2 should come out at the same time?

鑑於許多其他分析師已經深入研究了這個或那個特定項目的細節，我對你自己的理由和策略有更多的疑問。所以我將從 SEQUOIA 開始。我沒聽錯嗎，您的計劃是在 III 期試驗設計的同時披露即將到來的 SEQUOIA 數據綠色活檢？如果是這樣，你能告訴我為什麼這兩個應該同時出現的理由嗎？

And then secondarily, there's been a few people who've asked about your strategy around running CVOTs, which assets to hold on to or not. Can you give me a sense of what your ballpark estimate around the size, cost and the operational burden of a CVOT would be for you? And how you guys think about the number of studies of that scale that you could run for your assets simultaneously?

其次，有幾個人問過你關於運行 CVOT 的策略，哪些資產應該保留或不保留。你能告訴我你對 CVOT 的規模、成本和運營負擔的大概估計嗎？你們如何看待可以同時為您的資產運行的這種規模的研究數量？

Sure. So the first question is -- I've got more on the first question than the second question. So look, having a complete data set for SEQUOIA and having clarity on what the Phase III looks like just happened to come out at around the same time. And so it made sense for us to present both of those at the same time. And I think they're both related, of course, and they feed on each other, of course. If there was a big time delta between the 2, we would have been happy to separate those. But it just turns out that, again, the SEQUOIA data are analyzed and we expect to have final clarity on the Phase III data at about the same time.

當然。所以第一個問題是——我對第一個問題的了解比對第二個問題的了解要多。所以看，擁有完整的 SEQUOIA 數據集和清楚地了解第三階段的情況恰好同時出現。因此，我們同時展示這兩者是有意義的。我認為它們當然是相關的，而且它們當然是相互影響的。如果兩者之間有很大的時間差，我們會很樂意將它們分開。但事實證明，再次分析了 SEQUOIA 數據，我們預計大約在同一時間對 III 期數據進行最終澄清。

So it makes sense to do this together. And we'd like to do them in conjunction with Takeda, that makes sense as well. We'll just see when the calendars will align for that. With respect to the CVOT, look, we haven't given any guidance on how large a study would be and how much it would cost yet, in large part because we haven't had those end-of-Phase II meetings with the FDA. We really want to start to have these discussions before we opine on that because there are several ways you can do a CVOT, of course.

所以一起做這件事是有意義的。我們希望與武田一起合作，這也很有意義。我們將看看日曆何時會為此調整。關於 CVOT，你看，我們還沒有就一項研究的規模和成本給出任何指導，這在很大程度上是因為我們還沒有與 FDA 舉行那些 II 期末期會議.在我們發表意見之前，我們真的很想開始進行這些討論，因為當然，您可以通過多種方式進行 CVOT。

And it just feels a little bit early to opine on that. We will give guidance on that once we have it. But we just -- we're still pretty early here. We've got an interim look. We have a pretty good idea about what the data we think are telling us. And then we still are going to run these studies out to the end and then have end-of-Phase II meetings. And so I expect that next year sometime we can give you better guidance or some guidance on size, cost, et cetera, for the CVOT.

就此發表意見感覺有點早。一旦我們有了它，我們將給出指導。但我們只是 - 我們還很早。我們有一個臨時的外觀。對於我們認為的數據告訴我們的內容，我們非常清楚。然後我們仍然要將這些研究進行到最後，然後舉行第二階段結束會議。因此，我希望明年某個時候我們可以為 CVOT 提供更好的指導或一些關於規模、成本等方面的指導。

Can I ask one quick follow-up on that second half of that question?

我可以對該問題的後半部分進行快速跟進嗎？

Sure.

當然。

For HeFH in particular, how do you think about the appropriate patient population to study? There are a number of approved therapies out there, PCSK9 targeting and otherwise. But the universally available therapies varies pretty wildly across geographies, not in terms of approval, in terms of actual availability of patients, given reimbursement, et cetera, and real-life barriers.

特別是對於 HeFH，您如何看待合適的患者人群進行研究？有許多已獲批准的療法，包括 PCSK9 靶向療法和其他療法。但普遍可用的療法在不同地區差異很大，而不是在批准、患者的實際可用性、報銷等方面以及現實生活中的障礙方面。

So how do you think about the strategy between pursuing a study focused in areas where patients don't really have access to approved therapies versus a study, an add-on with approved therapies to allow you to access the U.S. and Western European market with more real world relevant data? How do you balance those 2? Would you do 2 CVOTs? Would you do 2 HeFH studies, is there someone to capture the 2 and 1 larger multi-arm study? Help me think about how you strategize and think about the likely outcomes for that path forward in that indication.

那麼，您如何看待針對患者無法真正獲得批准療法的領域開展研究與一項研究之間的策略，一項附加批准療法使您能夠以更多的方式進入美國和西歐市場現實世界的相關數據？你如何平衡這兩個？你會做2個CVOT嗎？你會做 2 項 HeFH 研究嗎？是否有人可以捕獲 2 項和 1 項更大的多臂研究？幫我想想你是如何制定戰略的，並考慮在該指示中前進道路的可能結果。

Yes. Again, this will be an (inaudible) answer to you, and I apologize. But until we start to have these interactions with the regulators, it's hard for us to know what -- it's hard for us to give you a good answer on that. Again, keep in mind that we're still -- we still haven't finished that study yet. We wanted to tell the Street as quickly as we could, where we think we can apply these 2 drugs. I think we've done that, but we're not yet ready to talk about how we would roll this out, where we'd roll this out, what sorts of studies would support these kind of -- these sort of populations until we start to have those interactions.

是的。同樣，這將是對您的（聽不清）答复，我深表歉意。但在我們開始與監管機構進行這些互動之前，我們很難知道是什麼——我們很難就此給你一個好的答案。再一次，請記住，我們仍然——我們還沒有完成這項研究。我們想盡快告訴華爾街，我們認為我們可以在哪裡應用這兩種藥物。我想我們已經做到了，但我們還沒有準備好談論我們將如何推出它，我們將在哪裡推出它，什麼樣的研究會支持這些——這些類型的人群，直到我們開始有那些互動。

And I am showing no further questions. I would now like to turn the call back over to Chris Anzalone for closing remarks.

我不再提出更多問題。我現在想將電話轉回給 Chris Anzalone 以作結束語。

Thanks, everyone, for joining us today. I hope everyone had a pleasant Thanksgiving holiday and have a nice larger holiday season. I apologize for the technical difficulties mid-call today, but we will talk to you soon.

謝謝大家今天加入我們。我希望每個人都度過了一個愉快的感恩節假期，並度過了一個愉快的假期。對於今天通話中出現的技術困難，我深表歉意，但我們會盡快與您交談。

This concludes today's conference call. Thank you for participating. You may now disconnect.

今天的電話會議到此結束。感謝您的參與。您現在可以斷開連接。