Arrowhead Pharmaceuticals Inc (ARWR) 2023 Q1 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。

Thanks so much. Good afternoon, and thank you for joining us today to discuss Arrowhead's results for its fiscal 2023 First Quarter ended December 31, 2022.

非常感謝。下午好，感謝您今天加入我們，討論 Arrowhead 截至 2022 年 12 月 31 日的 2023 財年第一季度業績。

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 Chief 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 Chief Commercial Officer; and Patrick O'Brien, our Chief Operating Officer and General Counsel, will 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 博士將提供我們中期和後期臨床管道的最新情況； James Hamilton 博士，我們的發現和轉化醫學主管，他將提供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，我們的首席商務官 Tracie Oliver；我們的首席運營官兼總法律顧問帕特里克·奧布萊恩 (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.

話雖如此，我想把電話轉給公司總裁兼首席執行官 Chris Anzalone。

Chris?

克里斯？

Thanks, Vince. Good afternoon, everyone, and thank you for joining us today. Arrowhead currently occupies a unique position within the biopharma world. I believe that RNAi is modality and our proprietary TRiM platform, in particular, are considered increasingly validated.

謝謝，文斯。大家下午好，感謝您今天加入我們。 Arrowhead 目前在生物製藥領域佔有獨特的地位。我相信 RNAi 是模式，尤其是我們專有的 TRiM 平台，被認為越來越有效。

RNAi is a potentially powerful way to treat many disease states. It appears to largely work as intended across numerous clinical studies, has the potential to be highly specific and has been generally well tolerated. Overlay on top of this, a scarcity premium. There is a clear scarcity of companies capable of developing RNAi therapeutics well and extreme scarcity of those capable of bringing RNAi outside the liver. These factors combined to position Arrowhead to create substantial value for our shareholders and the patients who rely on us for life altering new medicines.

RNAi 是治療許多疾病狀態的潛在有效方法。在眾多臨床研究中，它似乎在很大程度上按預期發揮作用，具有高度特異性的潛力，並且普遍具有良好的耐受性。在此之上疊加稀缺溢價。能夠很好地開發 RNAi 療法的公司非常稀缺，而能夠將 RNAi 帶到肝臟外的公司則極為稀缺。這些因素結合在一起，使 Arrowhead 能夠為我們的股東和依賴我們改變生活的新藥的患者創造可觀的價值。

I think this also frames how we should view Arrowhead currently, the progress we will discuss today and what these mean for the future. The 2 primary components of this sort of analysis are the ways in which we are expanding our technological reach and the ways in which we are leveraging our more proven technology. Let's begin with how we are expanding our reach. As you know, our pulmonary franchise is currently comprised of 3 clinical candidates, ARO-RAGE, ARO-MUC5AC and ARO-MMP7. With our announcement last week that the ARO-MMP7 Phase I/II study initiated, we are now treating subjects in all 3 programs. We remain on track to begin early data disclosures for ARO-RAGE and ARO-MUC5AC in the second quarter.

我認為這也構成了我們目前應該如何看待 Arrowhead、我們今天將討論的進展以及這些對未來意味著什麼。這種分析的兩個主要組成部分是我們擴大技術範圍的方式以及我們利用我們更成熟的技術的方式。讓我們從我們如何擴大影響範圍開始。如您所知，我們的肺部專營權目前由 3 個臨床候選藥物組成，ARO-RAGE、ARO-MUC5AC 和 ARO-MMP7。隨著我們上周宣布啟動 ARO-MMP7 I/II 期研究，我們現在正在治療所有 3 個項目的受試者。我們仍有望在第二季度開始 ARO-RAGE 和 ARO-MUC5AC 的早期數據披露。

This is an important milestone for us. We view the lungs as a target-rich environment and don't see 2 or 3 drugs coming out of that franchise, but rather potentially 8 or 9 as with hepatocytes, once we have clinical validation that we are able to address the cell side and reduce the expression of a target gene in a well-tolerated fashion. We believe that franchise will be substantially derisked. At that point, we have an expectation of success for future programs in terms of our ability to safely file the target gene. As such, clinical proof of concept in the first 1 or 2 programs within a cell type has a potential to unlock substantial value.

這對我們來說是一個重要的里程碑。我們將肺視為一個靶點豐富的環境，並沒有看到 2 或 3 種藥物從該專營權中脫穎而出，而是可能像肝細胞一樣有 8 或 9 種藥物，一旦我們進行了臨床驗證，我們能夠解決細胞側和以耐受性良好的方式降低靶基因的表達。我們認為特許經營將大大降低風險。到那時，就我們安全歸檔目標基因的能力而言，我們期望未來的項目能夠取得成功。因此，一種細胞類型中前 1 或 2 個程序的臨床概念驗證有可能釋放出巨大的價值。

We believe we will be there for our pulmonary franchise next quarter. And given what we learned with ARO-ENaC and our nonclinical data using ARO-RAGE, ARO-MUC5AC and ARO-MMP7 across several animal models, we are optimistic that we will see clinically relevant gene knockdown in a well-tolerated fashion. We have not spoken about our muscle-targeted franchise for some time, and I'm pleased to announce today that we intend to move ARO-DUX4 or candidates designed to treat facioscapulohumeral muscular dystrophy, or FSHD, into clinical studies next quarter. This is another example of our drive to apply RNAi to unmet medical needs wherever they are.

我們相信下個季度我們將在那裡獲得我們的肺部特許經營權。鑑於我們在 ARO-ENaC 中學到的知識以及我們在多個動物模型中使用 ARO-RAGE、ARO-MUC5AC 和 ARO-MMP7 的非臨床數據，我們樂觀地認為我們將以耐受良好的方式看到臨床相關的基因敲除。我們已經有一段時間沒有談論我們以肌肉為目標的特許經營權，今天我很高興地宣布，我們打算將 ARO-DUX4 或旨在治療面肩肱型肌營養不良症 (FSHD) 的候選藥物轉移到下個季度的臨床研究中。這是我們努力將 RNAi 應用於任何地方未滿足的醫療需求的另一個例子。

We have completed a large number of nonclinical studies, including acute and chronic GLP toxicity and we look forward to bringing this potentially important medicine to the patients who need it. Another important milestone relating to technology expansion that we expect next quarter, the disclosure of the next cell type we will be targeting and a presentation of our supporting nonclinical data. This and our work in the pulmonary and skeletal muscle spaces represent substantial growth opportunities for the company and would bring RNAi closer to reaching its full promise as a revolutionary therapeutic modality with the potential to address many new diseases. These programs are early, but they are the next great leaps forward for Arrowhead.

我們已經完成了大量的非臨床研究，包括急性和慢性 GLP 毒性研究，我們期待著將這種具有潛在重要意義的藥物帶給有需要的患者。另一個與我們預計下個季度的技術擴展相關的重要里程碑是我們將針對的下一個細胞類型的披露以及我們支持的非臨床數據的介紹。這一點以及我們在肺部和骨骼肌領域的工作為公司帶來了巨大的增長機會，並將使 RNAi 更接近於實現其作為一種具有解決許多新疾病潛力的革命性治療方式的全部承諾。這些計劃還很早，但它們是 Arrowhead 的下一個重大飛躍。

The second calendar quarter of 2023 is indeed a busy time for demonstrating Arrowhead innovation. Let's now turn to our liver programs. We have demonstrated across multiple candidates in many clinical studies and in thousands of patients that our liver-directed candidates appear to achieve high levels of target engagement and have encouraging safety and tolerability profiles. As such, we are focused on executing on our current liver programs and aggressively expanding our pipeline where we can. Last month, we announced top line results for the Phase II SEQUOIA clinical study of fazirsiran for the treatment of liver disease associated with alpha-1 antitrypsin deficiency. The active treatment arm had results that were highly consistent with the AROAAT2002 open-label study, which we previously published in the New England Journal of Medicine.

2023 年第二季度確實是展示 Arrowhead 創新的繁忙時期。現在讓我們轉向我們的肝臟程序。我們已經在許多臨床研究中的多個候選人和數千名患者中證明，我們的肝臟導向候選人似乎實現了高水平的目標參與，並具有令人鼓舞的安全性和耐受性。因此，我們專注於執行我們目前的肝臟項目，並在可能的情況下積極擴展我們的產品線。上個月，我們公佈了 fazirsiran 治療 alpha-1 抗胰蛋白酶缺乏症相關肝病的 SEQUOIA II 期臨床研究的主要結果。積極治療組的結果與我們之前發表在《新英格蘭醫學雜誌》上的 AROAAT2002 開放標籤研究高度一致。

Fazirsiran appears to be active against its targets with all treated patients achieving a high level of reduction of the mutant Z-AAT protein, which is known to be the root cause of AATD liver disease. This reduction over 12 months led to promising downstream changes in markers of liver disease, including reductions in inflammation and 50% of patients experienced a regression in fibrosis. These encouraging results are exactly what we had hoped for. The only data point that was a bit difficult to interpret was in the placebo arm.

Fazirsiran 似乎對其靶標有活性，所有接受治療的患者都實現了突變 Z-AAT 蛋白的高水平減少，已知 Z-AAT 蛋白是 AATD 肝病的根本原因。這種在 12 個月內的減少導致肝病標誌物的下游發生有希望的變化，包括炎症減少和 50% 的患者經歷了纖維化的消退。這些令人鼓舞的結果正是我們所希望的。唯一有點難以解釋的數據點是安慰劑組。

They are 3 of 8 patients with paired biopsies showed an improvement in fibrosis. We know that scoring fibrosis is a notoriously noisy measure and a way to smooth out such data is to ensure a large enough sample size. Unfortunately, with just 8 patients, a single patient in either direction can lead to confusing percentages. We believe that is what happened here.

他們是 8 名配對活檢顯示纖維化改善的患者中的 3 名。我們知道，纖維化評分是一項眾所周知的嘈雜措施，平滑此類數據的一種方法是確保樣本量足夠大。不幸的是，只有 8 名患者，任一方向的單個患者都可能導致令人困惑的百分比。我們相信這就是這裡發生的事情。

Fortunately, we can look to previous studies for guidance on what fibrosis should look like in untreated patients. For instance, the previous natural history study that followed over 50 AATD patients showed about 15% had improvement in fibrosis. We believe that the 50% of patients who showed improvement in fibrosis on fazirsiran, is a reliable measure because, a, the treatment groups had a larger sample size than placebo; and b, the improvements in fibrosis was part of a larger data set that made sense together.

幸運的是，我們可以參考以前的研究來指導未經治療的患者的纖維化情況。例如，之前對 50 多名 AATD 患者進行的自然歷史研究顯示，約 15% 的患者纖維化有所改善。我們認為 50% 的患者在接受 fazirsiran 治療後纖維化有所改善，這是一項可靠的衡量標準，因為 a，治療組的樣本量大於安慰劑組； b，纖維化的改善是一個更大的數據集的一部分，這些數據集在一起是有意義的。

Patients on fazirsiran had dramatic reductions in AAT monomer, globules, and they demonstrated decreased inflammation. The patients in the placebo arm showed none of these features. Takeda is now initiating a Phase III study that will enroll up to 160 patients, which is designed to be sufficiently large to smooth that variability to approximately the levels expected on natural history. Arrowhead is eligible to receive a milestone payment from Takeda when the Phase III study begins. During the previous quarter, 2 of our other partner programs generated milestone payments as they advanced into the next stage of development. Horizon Therapeutics enrolled the first subject in a Phase I study of HZN-457, formerly called ARO-XDH for the treatment of gout, earning Arrowhead a $15 million milestone payment.

使用 fazirsiran 的患者 AAT 單體、小球顯著減少，並且他們表現出炎症減少。安慰劑組的患者沒有表現出這些特徵。武田現在正在啟動一項 III 期研究，該研究將招募多達 160 名患者，該研究旨在足夠大以將這種變異性平滑到接近自然歷史預期的水平。當 III 期研究開始時，Arrowhead 有資格從武田獲得里程碑付款。在上一季度，我們的 2 個其他合作夥伴計劃在進入下一開發階段時產生了里程碑付款。 Horizon Therapeutics 在 HZN-457（以前稱為 ARO-XDH 用於治療痛風）的 I 期研究中招募了第一個受試者，為 Arrowhead 贏得了 1500 萬美元的里程碑付款。

In addition, we earned a $25 million milestone payment from Amgen after the first subject was enrolled in Amgen's Phase III trial of olpasiran for the treatment of cardiovascular disease. We believe in that program and in the potential of olpasiran to help patients with the risk of cardiovascular disease associated with elevated levels of Lp(a). However, with the recent presentation and publication of positive Phase II data, we determined that the timing was right to monetize our royalty stream associated with potential future olpasiran sales.

此外，在第一位受試者被納入安進公司用於治療心血管疾病的奧帕斯蘭 III 期試驗後，我們從安進公司獲得了 2500 萬美元的里程碑付款。我們相信該計劃以及 olpasiran 有可能幫助患有與 Lp(a) 水平升高相關的心血管疾病風險的患者。然而，隨著最近公佈和公佈的積極的 II 期數據，我們確定現在是時候將與未來潛在 olpasiran 銷售相關的特許權使用費貨幣化。

To that end, in exchange for rights to the olpasiran royalties, Royalty Pharma paid us $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 including the $25 million milestone payment I just mentioned. During the quarter, promising new clinical data across 3 late-breaking presentations were presented at the American Heart Association meeting on 3 investigational candidates for cardiometabolic diseases, ARO-APOC3, ARO-ANG3 and olpasiran.

為此，為了換取對 olpasiran 特許權使用費的權利，Royalty Pharma 預付了 2.5 億美元現金，並根據某些臨床、監管和銷售里程碑的實現支付了高達 1.6 億美元的額外款項。此外，我們保留了 Amgen 根據 2016 年許可協議可能到期的 4 億美元開發、監管和銷售里程碑付款的權利，包括我剛才提到的 2500 萬美元里程碑付款。在本季度，美國心臟協會會議上介紹了 3 項最新發表的有希望的新臨床數據，這些數據涉及 3 項心臟代謝疾病的研究候選人，ARO-APOC3、ARO-ANG3 和 olpasiran。

The totality of these data demonstrates the significant progress achieved in RNAi drug development, and they specifically suggest a potential future treatment paradigm where RNAi may be prominently leveraged in preventative cardiology. As I mentioned, a Phase III study has already been initiated with olpasiran. ARO-APOC3 is also being investigated in a Phase III study against FCS. And we expect that 48-week study to be fully enrolled next quarter. We also expect end of Phase II meetings this year to speak with the regulators about Phase III studies using ARO-APOC3 and SHTG patients as well as broad mixed dyslipidemia populations.

這些數據的整體證明了 RNAi 藥物開發取得的重大進展，它們特別提出了一種潛在的未來治療範式，其中 RNAi 可能在預防性心髒病學中得到顯著利用。正如我提到的，olpasiran 的 III 期研究已經啟動。 ARO-APOC3 也在針對 FCS 的 III 期研究中進行調查。我們預計下個季度將完成為期 48 週的研究。我們還預計今年 II 期會議結束時將與監管機構討論使用 ARO-APOC3 和 SHTG 患者以及廣泛的混合血脂異常人群的 III 期研究。

My expectation is that we will launch those Phase III studies at the end of the year. Similarly, I expect that we will move ARO-ANG3 into Phase III studies in familial hypercholesterolemia this year. I also expect several data presentations from 4 Phase II studies with these candidates throughout the year. Finally, we continue to make progress in our Phase I/II study of ARO-C3, our candidate designed to treat several complement-mediated diseases. I expect to release initial data next quarter. Janssen has also made progress with their Phase I study in JNJ-0795, our partnered candidate against NASH, and we expect a data disclosure that includes liver fat reduction this quarter.

我的期望是我們將在今年年底啟動這些 III 期研究。同樣，我預計今年我們會將 ARO-ANG3 轉移到家族性高膽固醇血症的 III 期研究中。我還期待全年對這些候選人進行的 4 項 II 期研究的一些數據介紹。最後，我們在 ARO-C3 的 I/II 期研究中繼續取得進展，我們的候選藥物旨在治療多種補體介導的疾病。我預計下個季度會發布初步數據。 Janssen 在 JNJ-0795 的 I 期研究也取得了進展，JNJ-0795 是我們針對 NASH 的合作候選藥物，我們預計本季度將披露包括減少肝臟脂肪在內的數據。

Turning to JNJ-3989, we have seen the media reports about Janssen deprioritizing HBV broadly, and that is consistent with our understanding. We have not received a termination letter for our license agreement, and it is our understanding that some legacy HBV studies are continuing, but we do not know where JNJ-3989 will ultimately end up. We will assess our options and rights when Janssen decides the path forward for the program. With that overview, I'd now like to turn the call over to Dr. Javier San Martin. Javier?

談到 JNJ-3989，我們看到媒體報導了楊森廣泛降低 HBV 的優先級，這與我們的理解是一致的。我們還沒有收到許可協議的終止函，據我們了解，一些遺留的 HBV 研究仍在繼續，但我們不知道 JNJ-3989 最終會在哪裡結束。當楊森決定該計劃的前進道路時，我們將評估我們的選擇和權利。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 describe the fazirsiran data that we presented last month and then give an update on where we are with these and late-stage studies of our cardiometabolic candidates.

謝謝克里斯，大家下午好。我想描述一下我們上個月提供的 fazirsiran 數據，然後更新我們在這些和我們的心臟代謝候選者的後期研究中的進展情況。

Chris mentioned earlier the SEQUOIA data from the treatment arms were very encouraging and consistent with the prior data generated from the 2002 open-label study. This is what we and our partner Takeda wanted to see. Patients receiving 25, 100 or 200 milligrams of fazirsiran who have baseline fibrosis demonstrated a dose-dependent NIM reduction in serum Z-AAT concentration at week 48 of 74%, 89% and 94%, respectively.

Chris 之前提到，來自治療組的 SEQUOIA 數據非常鼓舞人心，並且與 2002 年開放標籤研究產生的先前數據一致。這是我們和我們的合作夥伴武田希望看到的。接受 25、100 或 200 毫克 fazirsiran 且有基線纖維化的患者在第 48 週時表現出劑量依賴性 NIM 血清 Z-AAT 濃度分別降低 74%、89% 和 94%。

All 3 doses led to a dramatic reduction in total liver Z-AAT with a median reduction of 94% at the post baseline liver biopsy (inaudible). In addition, PAS+D globule burden, a histological measure of Z-AAT accumulation had a NIM reduction of 68%. Improvement in portal inflammation was offset in 42% of patients, while only 7% show worsening. Lastly, 50% of patients achieved an improvement in fibrosis of at least 1.5 METAVIR stage. In contrast, by week 48, patients receiving placebo who had baseline fibrosis saw no meaningful change from baseline in serum Z-AAT, had a 26% increase in liver Z-AAT and had no meaningful change in PAS-D globule burden. No placebo patients experienced an improvement in portal inflammation, while 44% experience worsened. 3 of the 8 placebo patients experienced an improvement in fibrosis at the post-baseline liver biopsies.

所有 3 種劑量均導致總肝臟 Z-AAT 顯著降低，基線肝活檢後的平均降低 94%（聽不清）。此外，PAS+D 球負荷（一種 Z-AAT 積累的組織學測量）使 NIM 降低了 68%。 42% 的患者門靜脈炎症的改善被抵消，而只有 7% 的患者出現惡化。最後，50% 的患者實現了至少 1.5 METAVIR 階段的纖維化改善。相比之下，到第 48 週時，基線纖維化的接受安慰劑的患者的血清 Z-AAT 與基線相比沒有顯著變化，肝臟 Z-AAT 增加了 26%，PAS-D 球負荷沒有顯著變化。沒有安慰劑患者出現門脈炎症改善，而 44% 的患者出現惡化。 8 名安慰劑患者中有 3 名在基線後肝活檢中經歷了纖維化改善。

This finding highlights the known variability on histological fibrosis assessment with a larger sample size, like in the planned Phase III study. The rate of improvement in patients receiving placebo may more closely approximate results from natural history study of untreated patients with AATD. Fazirsiran has been well-tolerated with treatment emergent adverse events reported today generally well balanced between fazirsiran and placebo groups. There were no treatment emergent adverse events leading to drug discontinuation, dose instructions or premature study withdrawals in any study group. Compared with placebo, no dose dependent of clinically meaningful changes while observing pulmonary function test over 1 year with fazirsiran.

這一發現突出了樣本量較大時組織學纖維化評估的已知變異性，就像計劃中的 III 期研究一樣。接受安慰劑的患者的改善率可能更接近未經治療的 AATD 患者的自然史研究結果。 Fazirsiran 耐受性良好，今天報告的治療緊急不良事件在 fazirsiran 和安慰劑組之間總體平衡。在任何研究組中都沒有導致停藥、劑量說明或過早退出研究的治療緊急不良事件。與安慰劑相比，使用 fazirsiran 觀察肺功能測試超過 1 年時，沒有劑量依賴性的臨床意義變化。

These are all encouraging signs for the program and for patients. We know this is a progressive disease of the liver caused by 1 thing, the accumulation of the mutant Z-AAT project which cannot efficiently get out of the liver. The data suggests that fazirsiran can reduce the protein of new Z-AAT and then the liver starts the process of breaking down and creating the accumulated Z-AAT in the liver, reducing inflammation and ultimate regress in fibrosis.

這些都是該計劃和患者令人鼓舞的跡象。我們知道這是一種由一件事引起的進行性肝臟疾病，突變體 Z-AAT 項目的積累無法有效地從肝臟中排出。數據表明，fazirsiran 可以減少新 Z-AAT 的蛋白質，然後肝臟開始分解並在肝臟中產生累積的 Z-AAT，從而減少炎症並最終使纖維化消退。

This is essentially the cascade of progressive liver disease in reverse. We believe that these can only start with the removal of insult to the liver which is the accumulation of a mutant Z-AAT protein. This data represents a hope for physicians under the patients with this disease who have no approved treatment options. We also announced that Takeda has initiated a randomized double-blind placebo-controlled Phase III study to evaluate the efficacy and safety of fazirsiran in patients with F2 to F4 fibrosis. Approximately 160 patients will be randomized one to one to receive fazirsiran or placebo.

這本質上是進行性肝病的反向級聯。我們認為，這些只能從消除對肝臟的損害開始，即突變 Z-AAT 蛋白的積累。該數據代表了治療沒有批准治療方案的這種疾病患者的醫生的希望。我們還宣布，武田已啟動一項隨機雙盲安慰劑對照 III 期研究，以評估 fazirsiran 在 F2 至 F4 纖維化患者中的療效和安全性。大約 160 名患者將一對一隨機分配接受 fazirsiran 或安慰劑。

The primary endpoint of this study is a decrease from baseline of at least 1 stage of histological fibrosis METAVIR staging in the central liver biopsy done at week 106 in patients with METAVIR stages reached to F2 or F3. I also wanted to give a brief update on where we are with our cardiometabolic candidates, ARO-APOC3 and ARO-ANG3. ARO-APOC3 is our investigational RNAi therapeutic targeting apolipoprotein C-III or APOC3 being developed as a treatment for patients with mixed dyslipidemia, severe hypertriglyceridemia and familial chylomicronemia syndrome. APOC3 is a key regulator of lipid and lipoprotein metabolic that inhibits lipoprotein lipase and mediates hepatic uptake of remnants particles in the LPL-independent pathway.

該研究的主要終點是在第 106 週時對 METAVIR 分期達到 F2 或 F3 的患者進行的中心肝活檢中，組織學纖維化 METAVIR 分期的至少 1 個階段從基線水平下降。我還想簡要介紹一下我們的心臟代謝候選藥物 ARO-APOC3 和 ARO-ANG3 的進展情況。 ARO-APOC3 是我們針對載脂蛋白 C-III 或 APOC3 的研究性 RNAi 治療藥物，正在開髮用於治療混合性血脂異常、嚴重高甘油三酯血症和家族性乳糜微粒血症綜合徵患者。 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 非依賴性途徑中殘留顆粒的肝臟攝取。

In clinical studies, ARO-APOC3 improve multiple lipid parameters and may provide clinical benefit in a broad population with dyslipidemia. For ARO-APOC3, we have the following ongoing studies: 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 study in patients with familial chylomicronemia syndrome. SHASTA-2 and MUIR are on schedule for data readout later this year.

在臨床研究中，ARO-APOC3 改善了多種脂質參數，並可能為廣大血脂異常人群提供臨床益處。對於 ARO-APOC3，我們正在進行以下研究：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綜合徵患者的 PALISADE III 期研究。 SHASTA-2 和 MUIR 按計劃在今年晚些時候進行數據讀取。

These studies will inform the development path, regulatory interactions and Phase III study design. PALISADE continued to enroll patients efficiently, and we believe we will achieve full enrollment in the second quarter of 2023. It is a year-long study, so this will allow study completion in Q2 2024. ARO-ANG3 is our investigational RNAi therapeutic designed to silence hepatic expression of angiopoietin-like protein 3 or ANGPTL3 being developed as a treatment for homozygous familial hypercholersterolemia or HoFH and heterozygous familial hypercholesterolemia or HeFH. ANGPTL3 is a key regulator of lipid and lipoprotein metabolism that initiated lipoprotein lipase and endothelial lipase. ARO-ANG3 has a unique mechanical function to address hypercholesterolemia distinct from other LDL-cholesterol lowering therapies. For ARO-ANG3, we have the following ongoing studies: the ARCHES-2 Phase II study in patients with mixed dyslipidemia and the GATEWAY Phase II study in patients with homozygous familial hypercholersterolemia.

這些研究將為開發路徑、監管相互作用和 III 期研究設計提供信息。 PALISADE 繼續有效地招募患者，我們相信我們將在 2023 年第二季度實現全面招募。這是一項為期一年的研究，因此這將允許研究在 2024 年第二季度完成。ARO-ANG3 是我們的研究性 RNAi 療法，旨在抑制血管生成素樣蛋白 3 或 ANGPTL3 的肝臟表達，用於治療純合子家族性高膽固醇血症或 HoFH 和雜合子家族性高膽固醇血症或 HeFH。 ANGPTL3 是啟動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。對於 ARO-ANG3，我們正在進行以下研究：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。

All patients in the ARCHES-2 have completed treatment and we should have data processed and analyzed in the middle of the year. GATEWAY is fully on goal, and we should have initial data around the middle of this year as well. We intend to interact with regulators about our plans for Phase III studies this year.

ARCHES-2 中的所有患者都已完成治療，我們應該在年中處理和分析數據。 GATEWAY 完全符合目標，我們也應該在今年年中左右獲得初步數據。我們打算與監管機構就我們今年的 III 期研究計劃進行互動。

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. We announced last week the initiation of a Phase I/II study of ARO-MMP7. So I want to talk about that first. ARO-MMP7 is designed to reduce expression of matrix metalloproteinase 7 or MMP7 as a potential treatment for idiopathic pulmonary fibrosis, or IPF. MMP7 is thought to play multiple roles in IPF pathogenesis, including promoting inflammation and aberrant epithelial repair in fibrosis. Significant unmet medical need exists for patients with IPF who experience progressive decline of lung function despite current therapies.

謝謝你，哈維爾。我們上周宣布啟動 ARO-MMP7 的 I/II 期研究。所以我想先談談這個。 ARO-MMP7 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 被認為在 IPF 發病機制中發揮多種作用，包括促進炎症和纖維化中的異常上皮修復。對於儘管採用當前療法仍經歷肺功能進行性下降的 IPF 患者，存在重大未滿足的醫療需求。

ARO-MMP7 1001 is a Phase I/IIa single ascending dose and multiple ascending dose study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of ARO-MMP7 in up to 56 healthy volunteers and in up to 21 patients with IPF. 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.

ARO-MMP7 1001 是一項 I/IIa 期單次遞增劑量和多次遞增劑量研究，旨在評估 ARO-MMP7 在多達 56 名健康志願者和多達 21 名 IPF 患者中的安全性、耐受性、藥代動力學和藥效學。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。

As Chris mentioned, we are on schedule to have initial data from the healthy volunteer portion of the Phase I/II studies in the first half of this year. The healthy volunteer portion of these studies has 2 parts, a single ascending dose part and a multiple ascending dose component. The studies are designed to assess safety and tolerability, pharmacokinetics and pharmacodynamics. We will be assessing pharmacodynamics by measuring available biomarkers in bronchoalveolar lavage fluid, induced sputum and for RAGE, we are also measuring serum sRAGE protein.

正如 Chris 提到的，我們將按計劃在今年上半年獲得 I/II 期研究的健康志願者部分的初步數據。這些研究的健康志願者部分有 2 個部分，一個遞增劑量部分和一個遞增劑量部分。這些研究旨在評估安全性和耐受性、藥代動力學和藥效學。我們將通過測量支氣管肺泡灌洗液、誘導痰中的可用生物標誌物來評估藥效學，對於 RAGE，我們還測量血清 sRAGE 蛋白。

The second portion of the studies is in patients with moderate to severe asthma. We recently initiated enrollment in asthma patient cohorts in both the ARO-MUC5AC and ARO-RAGE studies. Initial data should be available around the end of the year. Finally, moving on to ARO-C3, which is our investigational hepatocyte-targeted RNAi therapeutic targeting hepatic C3 expression as a potential treatment for complement-mediated hematologic and renal diseases. We remain on track to report data from part 1 of the study in healthy volunteers in the first half of this year.

研究的第二部分針對中度至重度哮喘患者。我們最近開始在 ARO-MUC5AC 和 ARO-RAGE 研究中招募哮喘患者隊列。初步數據應該在年底左右可用。最後，轉到 ARO-C3，這是我們正在研究的肝細胞靶向 RNAi 治療藥物，靶向肝 C3 表達，作為補體介導的血液病和腎臟疾病的潛在治療方法。我們仍有望在今年上半年報告健康志願者研究第 1 部分的數據。

Based on an analysis of data from the healthy volunteer single and multiple escalation dose cohorts, we anticipate selecting doses for the Park II open-label patient cohorts this month and we are on track to open patient cohort enrollment in the first half of this year. I will now turn the call over to Ken Myszkowski. Ken?

根據對健康志願者單次和多次遞增劑量隊列數據的分析，我們預計本月將為 Park II 開放標籤患者隊列選擇劑量，我們有望在今年上半年開放患者隊列登記。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 the quarter ended December 31, 2022, was $41.3 million or $0.39 per share based on 106 million fully diluted weighted average shares outstanding.

謝謝你，詹姆斯，大家下午好。正如我們今天報導的那樣，我們截至 2022 年 12 月 31 日的季度淨虧損為 4130 萬美元或每股 0.39 美元，基於 1.06 億股完全稀釋的加權平均流通股。

This compares with a net loss of $62.9 million or $0.60 per share based on 104.5 million fully diluted weighted average shares outstanding for the quarter ended December 31, 2021. Revenue for the quarter ended December 31, 2022, was $62.5 million compared to $27.4 million for the quarter ended December 31, 2021. Revenue in the current period primarily relates to our collaboration agreements with Amgen, Horizon and Takeda. Revenues 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.

相比之下，截至 2021 年 12 月 31 日止季度的淨虧損為 6290 萬美元或每股 0.60 美元，基於 1.045 億股完全稀釋的加權平均流通股。截至 2022 年 12 月 31 日止的季度收入為 6250 萬美元，而同期為 2740 萬美元截至 2021 年 12 月 31 日的季度。當期收入主要與我們與 Amgen、Horizon 和 Takeda 的合作協議有關。在我們完成履行義務時確認收入，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 $107 million of revenue be recognized associated with the Takeda collaboration, which we anticipate will be recognized over the next 1 to 2 years. Additionally, Horizon enrolled the first subject in a Phase I trial of HZN-457, formerly known as ARO-XDH, which triggered a $15 million milestone payment to us, and Amgen enrolled the first subject in its Phase III registrational trial of olpasiran, which triggered a $25 million milestone payment to us. Both milestone payments were received in the second quarter of fiscal 2023 (sic)[2022].

與武田合作相關的收入仍有 1.07 億美元待確認，我們預計這將在未來 1 至 2 年內確認。此外，Horizon 在 HZN-457（以前稱為 ARO-XDH）的 I 期試驗中招收了第一個受試者，這觸發了向我們支付 1500 萬美元的里程碑付款，而安進在其 olpasiran 的 III 期註冊試驗中招收了第一個受試者，這向我們觸發了 2500 萬美元的里程碑付款。兩項里程碑付款均於 2023 財年第二季度（原文如此）[2022] 收到。

Revenue in the prior period primarily related to the recognition of a portion of the payments received from our license and collaboration agreements with Takeda and Horizon. Total operating expenses for the quarter ended December 31, 2022, were $104.7 million compared to $90.8 million for the quarter ended December 31, 2021. The key driver in this change was increased candidate costs and salaries as the company's pipeline of clinical candidates has both increased and advanced into later stages of development. Net cash used by operating activities during the quarter ended December 31, 2022, was $75.5 million compared to $61.3 million for the quarter ended December 31, 2021. The increase in cash used by operating activities is driven primarily by higher research and development expenses.

前期收入主要與確認從我們與武田和 Horizon 的許可和合作協議中收到的部分付款有關。截至 2022 年 12 月 31 日的季度總運營費用為 1.047 億美元，而截至 2021 年 12 月 31 日的季度為 9080 萬美元。這一變化的主要驅動因素是候選人成本和工資的增加，因為公司的臨床候選人管道都增加了並進入後期發展階段。截至 2022 年 12 月 31 日的季度，經營活動使用的現金淨額為 7550 萬美元，而截至 2021 年 12 月 31 日的季度為 6130 萬美元。經營活動使用的現金增加主要是由於研發費用增加所致。

We expect our operating cash burn to be $70 million to $90 million per quarter in fiscal 2023 and capital expenditures up to $200 million as we approach completion on our footprint expansion projects, including GMP manufacturing. Turning to our balance sheet. Our cash and investments totaled $617.6 million at December 31, 2022 compared to $482.3 million at September 30, 2022.

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，隨著我們接近完成足跡擴張項目（包括 GMP 製造），資本支出將達到 2 億美元。轉向我們的資產負債表。截至 2022 年 12 月 31 日，我們的現金和投資總額為 6.176 億美元，而 2022 年 9 月 30 日為 4.823 億美元。

The increase in our cash and investments was primarily related to the $250 million payment from Royalty Pharma, offset by our operating cash burn along with continuing capital projects. Our common shares outstanding at December 31, 2022, were 106.1 million.

我們現金和投資的增加主要與來自 Royalty Pharma 的 2.5 億美元付款有關，被我們的運營現金消耗以及持續的資本項目所抵消。截至 2022 年 12 月 31 日，我們的已發行普通股為 1.061 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. We're making good progress on our 20 in '25 initiative, where we expect to have 20 individual drug candidates in clinical trials or at market in the year 2025. We currently have 12 drug candidates in clinical studies, 6 of which are wholly owned and 6 are partnered.

謝謝，肯。我們在 20 in '25 計劃中取得了良好進展，我們預計在 2025 年將有 20 種候選藥物進入臨床試驗或上市。我們目前有 12 種候選藥物處於臨床研究中，其中 6 種是全資擁有的和 6 個是合作夥伴。

I expect that 12 to become 15 or 16 by the end of this year. I mentioned ARO-DUX4 moving into the clinic next quarter, and I expect 2 or 3 additional new drug candidates this year and we have never talked about them publicly. Having such a large clinical pipeline provides us with a broad base for which to build value and spread risk, and it also gives us consistent opportunities to share data and progress.

我預計到今年年底，12 個將變成 15 個或 16 個。我提到 ARO-DUX4 下個季度進入臨床，我預計今年會有 2 或 3 個新的候選藥物，我們從未公開談論過它們。擁有如此龐大的臨床管道為我們創造價值和分散風險提供了廣泛的基礎，也為我們提供了共享數據和進展的持續機會。

In the near term, we think these opportunities will include the following: Phase I NASH data from JNJ-0795 this quarter, fazirsiran SEQUOIA full 12-month biopsy data in the second quarter, initiation of ARO-HSD Phase IIb in Q1 or Q2, early ARO-RAGE Phase I/II data in the second quarter, early ARO-MUC5AC Phase I/II data in the second quarter, early ARO-C3 Phase I/II data in the second quarter, initiation of the ARO-DUX4 Phase I/II study in the second quarter, disclosure of our next cell type and supporting data in the second quarter, ARO-APOC3 data throughout the year, ARO-ANG3 data throughout the year, initiation of 2 to 3 new Phase I studies toward the end of the year, initiation of JNJ-0795 Phase II in Q3 or Q4, early ARO-MMP7 data in Q4, initiation of ARO-ANG3 Phase III studies in Q4 and initiation of additional ARO-APOC3 Phase III studies in Q4.

在短期內，我們認為這些機會將包括以下內容：本季度 JNJ-0795 的 I 期 NASH 數據，第二季度 fazirsiran SEQUOIA 完整的 12 個月活檢數據，第一季度或第二季度啟動 ARO-HSD IIb 期，第二季度早期 ARO-RAGE I/II 期數據，第二季度早期 ARO-MUC5AC I/II 期數據，第二季度早期 ARO-C3 I/II 期數據，ARO-DUX4 I 期啟動/二季度研究，二季度披露我們的下一個細胞類型和支持數據，全年ARO-APOC3數據，全年ARO-ANG3數據，年底啟動2到3個新的I期研究今年的第 3 季度或第 4 季度啟動 JNJ-0795 II 期研究，第 4 季度啟動 ARO-MMP7 早期數據，第 4 季度啟動 ARO-ANG3 III 期研究，第 4 季度啟動額外的 ARO-APOC3 III 期研究。

As you can see, we expect a busy 2023. Thank you for joining us today, and I would now like to open the call to questions. Operator?

如您所見，我們預計 2023 年會很忙。感謝您今天加入我們，現在我想開始提問。操作員？

Our first question comes from the line of Ellie Merle of UBS.

我們的第一個問題來自瑞銀集團的 Ellie Merle。

Just in terms of the data in the second quarter from the pulmonary franchise, I guess, what exactly are we getting in terms of the number of patients and dose levels? And what are you looking to see, I guess, what degree of lowering at phase used dose levels are sort of the target levels that you're looking for and will confirm, I guess, kind of this target engagement that we're hoping to see?

就肺部專營權第二季度的數據而言，我想，我們在患者數量和劑量水平方面究竟得到了什麼？我想你想看到什麼，階段使用劑量水平的降低程度是你正在尋找的目標水平，我想將確認我們希望的這種目標參與看？

So look, I don't know that we have a target knockdown threshold that we're looking for. This is our first -- this will be our first data in the UN subjects. So we're looking to see what sort of knockdown we catch. Again, I don't know that we have . James, do you want to talk about some of the cohorts what have you seen?

所以看，我不知道我們是否有我們正在尋找的目標擊倒閾值。這是我們的第一個——這將是我們在聯合國主題中的第一個數據。所以我們想看看我們能捕捉到什麼樣的擊倒。同樣，我不知道我們有 .詹姆斯，你想談談你看到的一些隊列嗎？

Sure, right. So the -- we'll have data in the SAD cohorts for the first 4 dose levels and then likely as well the MAD cohorts through at least the first 3 cohorts, the 2 dose cohorts. That's all in the healthy volunteers. We won't have any patient data at that point.

當然，對。所以——我們將在 SAD 隊列中獲得前 4 個劑量水平的數據，然後可能還有 MAD 隊列中至少前 3 個隊列的數據，即 2 個劑量隊列。這就是健康志願者的全部。那時我們不會有任何患者數據。

(Operator Instructions) Our next question comes from the line of Maury Raycroft of Jefferies.

（操作員說明）我們的下一個問題來自 Jefferies 的 Maury Raycroft。

I had a question about the pulmonary data as well. Wondering if you expect the bronchial lavage data to correspond with the RAGE serum PD biomarker data. I guess, maybe you talk a little bit more on just what kind of proof of concept we should be looking for in this update.

我也有關於肺部數據的問題。想知道您是否期望支氣管灌洗數據與 RAGE 血清 PD 生物標誌物數據一致。我想，也許你會多談談我們應該在這次更新中尋找什麼樣的概念證明。

James?

詹姆士？

Yes. I think directionally, I would expect, based on what we've seen in animals and monkeys specifically that the lavage data should -- sRAGE lavage data should directionally behave the same as the serum data.

是的。我認為方向性的，我希望，根據我們在動物和猴子身上看到的具體情況，灌洗數據應該——sRAGE 灌洗數據應該與血清數據在方向上表現相同。

And my thinking on that is that we will see what they look like. But my sense is that the lavage data make give us more accurate knockdown because it's local, of course. The challenge with the systemic is that there may be extra pulmonary sources of RAGE. And so that may muddy the data a bit. But that will give us better idea of duration because we're not these individuals more than once.

我的想法是，我們將看到它們的樣子。但我的感覺是，灌洗數據可以讓我們更準確地擊倒，因為它當然是本地的。全身性的挑戰在於可能存在額外的 RAGE 肺來源。所以這可能會使數據有點混亂。但這會讓我們更好地了解持續時間，因為我們不止一次成為這些人。

Got it. Okay. That's helpful. And also just with the JNJ media reports, I'm wondering if you've had any discussions with JNJ regarding 3989 ongoing studies and have a sense of when they could make a decision on the program? And what are some options you're considering if JNJ terminates the license agreement?

知道了。好的。這很有幫助。而且就 JNJ 媒體報導而言，我想知道您是否與 JNJ 就 3989 項正在進行的研究進行過任何討論，並且了解他們何時可以對該項目做出決定？如果 JNJ 終止許可協議，您正在考慮哪些選擇？

So this is all new for us. And so I don't have too much to comment on this at this point. Again, we understand that they are deprioritizing HBV broadly, this doesn't have anything to do with our candidate as I understand it. And so they do not have -- again, my understanding -- and Patrick O'Brien can correct me if I'm wrong, my understanding is that they don't have the right to sublicense this, but they could assign it. And so we'll see what they decide to do there. If they do decide to assign it, it requires our approval, otherwise it will come back to us.

所以這對我們來說是全新的。因此，此時我對此沒有太多評論。同樣，我們了解到他們正在廣泛地降低 HBV 的優先級，這與我理解的我們的候選人沒有任何關係。因此，他們沒有——再一次，我的理解——如果我錯了，Patrick O'Brien 可以糾正我，我的理解是他們無權再許可這個，但他們可以分配它。因此，我們將看看他們決定在那裡做什麼。如果他們確實決定分配它，則需要我們的批准，否則它會退還給我們。

So we don't know what their goals are here, and we'll just have to wait to see. But look, we believe in that program. I think that drug clearly does what it is designed to do. We're seeing substantial reduction in viral antigens. I think that's important that, that is maybe the critical component to getting to a functional cure. It's not the only component, but I think it's the critical one, and they were interrogating a number of different strategies to see what they can combine with that to get to functional cures. We look forward to seeing more of those data because we are only so close to it at this point, of course.

所以我們不知道他們的目標是什麼，我們只能拭目以待。但是看，我們相信那個程序。我認為該藥物顯然可以發揮其設計作用。我們看到病毒抗原大幅減少。我認為這很重要，這可能是實現功能性治癒的關鍵組成部分。它不是唯一的組成部分，但我認為它是關鍵的組成部分，他們正在審視許多不同的策略，看看他們可以將什麼與這些策略結合起來，以實現功能性治療。當然，我們期待看到更多這樣的數據，因為我們目前離它如此之近。

Our next question comes from the line of Mayank Mamtani of B. Riley.

我們的下一個問題來自 B. Riley 的 Mayank Mamtani。

Looks like a busier year 2023 for you than last year. So maybe just following up on the pulmonary programs. On the safety and tolerability data that we'll have for RAGE and MUC5AC, could you talk about sort of the implications of that broadly for your delivery system? And just maybe remind us of the nebulizer system is the same across the different programs. And a second part question on the MMP7. What is the frequency of administration you're looking to target there? As you know, in IPF, now there's a lot of progress in the pipeline with some antibody approaches also coming in.

看起來 2023 年對你來說比去年更忙。所以也許只是跟進肺部計劃。關於我們將獲得的 RAGE 和 MUC5AC 的安全性和耐受性數據，您能否談談這對您的遞送系統的廣泛影響？也許只是提醒我們霧化器系統在不同的程序中是相同的。第二部分是關於 MMP7 的問題。您希望那裡的管理頻率是多少？如您所知，在 IPF 中，現在管道中取得了很多進展，一些抗體方法也出現了。

Sure. Yes. So I think the safety data that we will have for RAGE and MUC5AC, I think while it will be candidate specific and target specific, I think will be applicable to the broader platform and will help to support the pulmonary delivery platform generally. In terms of the nebulizer question, this is -- it's the same nebulizer system that we're using across the 3 different programs. It's different than what we used with ARO-ENaC. So this is a more efficient nebulizer versus what we used with ENaC. And then there was a third question there, I think...

當然。是的。所以我認為我們將擁有的 RAGE 和 MUC5AC 的安全數據，我認為雖然它是特定於候選人和目標的，但我認為將適用於更廣泛的平台，並將有助於普遍支持肺部給藥平台。就霧化器問題而言，這與我們在 3 個不同程序中使用的霧化器系統相同。它與我們使用的 ARO-ENaC 不同。因此，與我們與 ENaC 一起使用的霧化器相比，這是一種更高效的霧化器。然後還有第三個問題，我想……

MMP7 dose interval.

MMP7 劑量間隔。

So the initial dosing interval for MMP7 is every 2 weeks in the MAD cohorts. In the SAD, of course, we just do single doses, but then we're investigating day 1, 15 and 29 in MMP7 similar to what we're doing in the MAD cohorts for MUC5AC. Now that may not be the dosing regimen going forward. That's sort of a more intensive regimen consistent with what we used in the animals to generate maximum knockdown. We'll have to see what the duration of knockdown is after both a single dose and after the multi-dose administration.

因此，在 MAD 隊列中，MMP7 的初始給藥間隔是每 2 週一次。當然，在 SAD 中，我們只進行單次給藥，但隨後我們在 MMP7 中研究第 1、15 和 29 天，類似於我們在 MUC5AC 的 MAD 隊列中所做的。現在這可能不是未來的給藥方案。這是一種更強化的方案，與我們在動物身上使用的方案一致，以產生最大的擊倒效果。我們必須看看在單劑量和多劑量給藥後擊倒的持續時間是多少。

Got it. And then just a quick follow-up on JNJ-0795. Could you just remind us what the target there is and sort of the progress how far along that program is? I know it's a JNJ partner program. And then just broadly on the -- on sort of the partnership with JNJ, is it sort of program by program, I'm assuming and whatever happens with 3989 has no implications on how things may progress with 0795?

知道了。然後只是對 JNJ-0795 的快速跟進。您能否提醒我們目標是什麼以及該計劃的進展情況？我知道這是 JNJ 合作夥伴計劃。然後就廣泛而言 - 關於與 JNJ 的合作夥伴關係，它是否是一個項目一個項目，我假設 3989 發生的任何事情都不會影響 0795 的進展情況？

Yes, those are different divisions within Janssen. The target is PNPLA3, a -- gosh, maybe the most genetically validated target for NASH. They are in a Phase I study that includes SAD as well as the MAD portion. And it is my expectation that we can start to report at least some -- not at least, certainly some SAD data this quarter.

是的，這些是 Janssen 內部的不同部門。目標是 PNPLA3，天哪，也許是 NASH 最有效的基因目標。他們正在進行包括 SAD 和 MAD 部分的第一階段研究。我期望我們可以開始報告至少一些 - 至少，當然是本季度的一些 SAD 數據。

Our next question comes from the line of Joe Beatty of Baird.

我們的下一個問題來自 Baird 的 Joe Beatty。

So for the lung programs and the data coming in Q2, could you elaborate how meaningful the data is for other programs? In the prepared remarks, you talked about 8 or 9 programs that could come for long. How derisking as this data that we get in Q2?

那麼對於肺部項目和第二季度的數據，你能否詳細說明這些數據對其他項目的意義？在準備好的發言中，您談到了 8 或 9 個可能會長期存在的項目。我們在第二季度獲得的數據有多低風險？

I think it's substantially derisking. This is the -- this will be the first clinical data from our lung franchise. The structure of these candidates is really quite similar between MMP7, MUC5AC, RAGE, and future ones. They are simple conjugates, as you know. It's simple RNAi trigger that is chemically modified linked to targeting moiety. And so to the extent that it is well tolerated and can get into these pulmonary epithelial cells, I think it is telling as it relates to future candidates. These cells don't care what the sequence of the RNAi trigger is. Once you get into the cell and get loaded into the risk complex, it could be any sequence. So I think that it is a substantial derisking event, again, to the extent that we do show clinically relevant knockdown in a well-tolerated fashion.

我認為這大大降低了風險。這是——這將是我們肺部專營權的第一份臨床數據。這些候選人的結構在 MMP7、MUC5AC、RAGE 和未來的候選人之間非常相似。如您所知，它們是簡單的結合物。它是簡單的 RNAi 觸發器，經過化學修飾與靶向部分相連。因此，就其耐受性良好並且可以進入這些肺上皮細胞的程度而言，我認為這與未來的候選人有關。這些細胞不關心 RNAi 觸發器的序列是什麼。一旦你進入單元並加載到風險複合體中，它可以是任何序列。因此，我認為這再次是一個實質性的去風險事件，就我們確實以良好耐受的方式顯示臨床相關的擊倒而言。

Great. That's helpful. And then for AAT, are you going to discuss the powering assumptions or otherwise, just kind of speak at a high level as to what gives you confidence in the powering for the 160-patient registrational Phase III at this plan?

偉大的。這很有幫助。然後對於 AAT，您是要討論供電假設還是其他方式，只是在高層次上談談是什麼讓您對該計劃的 160 名患者註冊 III 期供電充滿信心？

Yes. I can give you a high-level concept, but this is Takeda's protocol design and is already in the public domain clinicaltrials.gov. But essentially, if you look at what Takeda has been thinking is taking a conservative approach for the active treatment group, and not as conservative for the placebo group.

是的。我可以給你一個高層次的概念，但這是武田的協議設計，並且已經在公共領域 clinicaltrials.gov 中。但本質上，如果你看看武田一直在想的是對積極治療組採取保守的方法，而不是對安慰劑組採取保守的方法。

But with that made the assumptions and the typical standard deviation that are expected and with that in mind with power calculation, they took, we think, good and conservative approach with regard to the duration, which is 106 weeks, so 2 years essentially and the sample size and the patient population they selected. So it's not just the assumption, but is the assumption in the context of sample size of 160 patients, a 2-year observation and all patients we have at least in F2 fibrosis stage based on METAVIR. So when you look at the totality of the study design, we believe this study is well set to show the benefit in fibrosis levels. And then the details for Takeda eventually will come out with more details.

但是，根據這些假設和預期的典型標準偏差，並考慮到功效計算，我們認為，他們在持續時間方面採取了良好和保守的方法，即 106 週，所以基本上是 2 年，樣本量和他們選擇的患者群體。所以這不僅僅是假設，而是在 160 名患者的樣本量、2 年觀察和我們至少處於基於 METAVIR 的 F2 纖維化階段的所有患者的背景下的假設。因此，當您查看研究設計的整體時，我們相信這項研究已經準備好展示纖維化水平的益處。然後武田的細節最終會公佈更多細節。

Our next question comes from the line of Madhu Kumar of Goldman Sachs.

我們的下一個問題來自高盛的 Madhu Kumar。

So I guess our first one relates to the idea in the lung of which cell type matters? And how do you think about in various pulmonary indications targeting the lung epithelia cells in the lung epithelium versus, say, other cell types that are just present in the lung, particularly immune cells in the lung. How do you kind of thread that needle.

所以我想我們的第一個與肺中哪種細胞類型重要的想法有關？您如何看待針對肺上皮細胞中肺上皮細胞的各種肺部適應症與僅存在於肺中的其他細胞類型，特別是肺中的免疫細胞。你是怎麼穿那根針的。

And then kind of secondly, along the question of threading the needle, how do you think of Goldilocks phenomenon of knockdown. So these pretty powerful inflammatory modulars where you want to suppress them enough so that you reduce the kind of autoimmune functions, but you don't suppress them so much that you reduce the viral protective functions. How do you think about kind of that data balance?

其次，關於穿針引線的問題，您如何看待 Goldilocks 擊倒現象。所以這些非常強大的炎症模塊，你想充分抑制它們，以便減少自身免疫功能的種類，但你不會過度抑制它們，以至於降低病毒保護功能。您如何看待這種數據平衡？

Sure. So well, first of all, regarding the epithelial cells that are the cells that we're trying to target, those are generally the cell types where we're looking for targets. So we're looking for targets that are expressed by lung epithelial cells. And if there's a target that is related to a disease that we could knock down. That's the ideal situation.

當然。好吧，首先，關於我們試圖瞄準的上皮細胞，這些細胞通常是我們正在尋找目標的細胞類型。所以我們正在尋找由肺上皮細胞表達的靶標。如果有一個目標與我們可以擊倒的疾病有關。那是最理想的情況。

I think that's where our system performs the best is in getting into those cell types and knocking down targets expressed in pulmonary epithelial cells or some of the derivatives, something like the basaloid cells in -- that are more specific to an IPF patient population.

我認為這就是我們的系統表現最好的地方是進入這些細胞類型並敲除在肺上皮細胞或一些衍生物中表達的靶標，比如基底樣細胞——它們對 IPF 患者群體更具特異性。

Right now, we are not targeting any gene targets in macrophages or other immune cells in the lung. We're pretty focused on the epithelial or epithelia cell-derived types of cells. And then the other question was about modulating inflammation. So for something like RAGE that knocking down RAGE, like you said, could be fairly powerful as an anti-inflammatory. There are other -- there's redundancies built into the system. So I think some of the innate immune functions that would be inhibited by silencing RAGE can also be activated through a TLR-4 pathway. So you're not completely wiping out the innate immune system altogether. There is some redundancy there.

目前，我們並未針對巨噬細胞或肺部其他免疫細胞中的任何基因靶點。我們非常關注上皮細胞或上皮細胞衍生的細胞類型。然後另一個問題是關於調節炎症。所以對於像 RAGE 這樣的東西，像你說的那樣擊倒 RAGE 可能是相當強大的抗炎藥。還有其他 - 系統中內置了冗餘。所以我認為一些會被沉默 RAGE 抑制的先天免疫功能也可以通過 TLR-4 通路被激活。所以你並沒有完全消滅先天免疫系統。那裡有一些冗餘。

Our next question comes from the line of Mani Foroohar of SVB.

我們的下一個問題來自 SVB 的 Mani Foroohar。

This is (inaudible). First question, we had a question regarding the pulmonary program. What would be the level of knockdown that will be expected in order to reach functional benefit in the clinical setting?

這是（聽不清）。第一個問題，我們有一個關於肺部計劃的問題。為了在臨床環境中獲得功能性益處，預期的敲低水平是多少？

We don't know the answer to that. There are advantages and disadvantages to being pioneers here. The advantages are to be the first ones. The disadvantages are that no one's done this before. And so we'll be learning the field as we go. So I don't have a good answer for you on that, unfortunately.

我們不知道答案。在這方面做先驅有好處也有壞處。優點是排在第一位。缺點是以前沒有人這樣做過。因此，我們將邊走邊學這個領域。不幸的是，我沒有很好的答案給你。

All right, I guess we'll have to ask again a little later. And so I guess maybe just a different question in terms of the HBV program. So should the assets be returned by JNJ, what would be your development plan? Would you consider -- given that most assets in this particular sector or partners, especially for the JNJ combination program, would you consider developing it internally or seeking out a new partner?

好吧，我想我們得過一會兒再問。所以我想可能只是關於 HBV 計劃的一個不同問題。那麼如果JNJ歸還資產，你們的發展計劃是什麼？你會考慮——鑑於這個特定部門或合作夥伴的大多數資產，特別是對於 JNJ 組合計劃，你會考慮在內部開發它還是尋找新的合作夥伴？

Yes, that's a good question. So look, again, as I mentioned, that drug is doing what it's designed to do, and that's exciting. Janssen has done a phenomenal job with a number of very large studies. And so they're sitting on a ton of data. We are familiar with some of those data, but not all of them. And so it's hard for us to make -- it's impossible for us to make a decision about how we might develop that drug until we get into those data.

是的，這是個好問題。所以再一次看，正如我提到的，這種藥物正在發揮其設計的作用，這令人興奮。 Janssen 在許多非常大的研究中做了出色的工作。所以他們坐擁大量數據。我們熟悉其中一些數據，但不是全部。因此，我們很難做出——在我們獲得這些數據之前，我們不可能就如何開發這種藥物做出決定。

We are certainly interested again because the drug appears to be doing what we intended it to do. And so we just have to take a look at all the data to see what the path forward will be. I do firmly believe that there is a path forward. I just don't know what it is until we see the data.

我們當然再次感興趣，因為這種藥物似乎在做我們想要做的事情。因此，我們只需要查看所有數據即可了解前進的道路。我堅信有一條前進的道路。在我們看到數據之前，我只是不知道它是什麼。

And I guess, lastly, would there be any sense of timing in terms of when you'd be able to either get maybe more clarity from JNJ or access to the data so you could make an informed decision?

我想，最後，就何時能夠從 JNJ 獲得更清晰的信息或訪問數據以便做出明智的決定而言，是否會有任何時間感？

I don't have an answer for that, unfortunately. I don't know what their time line is. As I mentioned in prepared remarks, my understanding is that there are some ongoing studies. I assume that those are still ongoing, but I don't know, to be honest. I think this is all happening real time, and my expectation is that we'll have better clarity from Janssen over the next coming weeks.

不幸的是，我對此沒有答案。我不知道他們的時間表是什麼。正如我在準備好的發言中提到的，我的理解是有一些正在進行的研究。我認為這些仍在進行中，但老實說，我不知道。我認為這一切都是實時發生的，我希望在接下來的幾週內我們能從 Janssen 那裡得到更清晰的信息。

Our next question comes from the line of Luca Issi of RBC Capital Markets.

我們的下一個問題來自 RBC Capital Markets 的 Luca Issi。

I have 2. Maybe circling on A1AT, circling back on the prior question, Javier. Can you just talk a little bit more about the powering assumption here in the Phase III at 160 patients in the primary endpoint of 2 years, what is the minimum delta in fibrosis between the active arm and placebo that is actually sufficient to hit the stat? Any color there would be great. And then maybe on DUX4, can you just talk a little bit more about that program? I think in the past, you have mentioned that expression could be quite variable there. So wondering how you're planning to mitigate their risk and maybe more broadly how confident are you in that program?

我有 2 個問題。也許在 A1AT 上打轉，然後回到前面的問題，Javier。您能否多談談 III 期中 160 名患者在 2 年的主要終點中的動力假設，活性組和安慰劑之間實際上足以達到統計數據的最小纖維化增量是多少？任何顏色都會很棒。然後也許在 DUX4 上，你能多談談那個程序嗎？我想在過去，你提到過那裡的表達可能非常多變。所以想知道您打算如何降低他們的風險，也許更廣泛地說，您對該計劃的信心如何？

Yes. Luca, so I don't know how much detail I can provide on the specifics that the Takeda team and the statistician, the work they did to power the study or to size the study with 160 patients. And like I said, the primary endpoint or the primary analysis is at 2 years or 106 weeks when all patients with F2 and F3 that would be about 110 or so complete the 2-year study. So that gives you really for what we learned so far and we can take this 50% reduction in fibrosis that we observed twice in 2 different studies with the same and similar patient population as a good point of reference, I would say.

是的。盧卡，所以我不知道我能提供多少關於武田團隊和統計學家的細節，他們為推動研究或確定 160 名患者的研究規模所做的工作。就像我說的，主要終點或主要分析是在 2 年或 106 週時，屆時所有 F2 和 F3 患者大約有 110 名左右完成 2 年研究。因此，這確實為您提供了我們迄今為止所學到的知識，我們可以將我們在 2 項不同研究中兩次觀察到的相同和相似患者群體的纖維化減少 50% 作為一個很好的參考點，我想說。

And then you need to look at the natural history data versus the SEQUOIA data and go somewhere in between. And if you do that exercise, you will come out with the same number, more likely. So that's how I will address this comment and...

然後你需要查看自然歷史數據與 SEQUOIA 數據，並在兩者之間進行比較。如果你做那個練習，你會得到相同的數字，更有可能。所以這就是我將如何處理這個評論和......

And importantly, as Javier mentioned that, that 2-year time point is at around 110 patients, not the full 160. And importantly, it was powered based on that. So given their assumptions, they determined that 110 should be sufficient. James, you want to...

重要的是，正如 Javier 提到的那樣，2 年的時間點是大約 110 名患者，而不是全部 160 名患者。重要的是，它是基於此提供動力的。因此，根據他們的假設，他們確定 110 應該足夠了。詹姆斯，你想...

Sure. Yes, the DUX question. It's correct that the expression of DUX4 is stochastic. And so the measurement of the protein in the muscle and the downstream DUX4 affected genes can be challenging as at least one other company has demonstrated and that was one of the reasons, if you recall, that we wanted to be sure that we had the tox coverage to cover a longer Phase II study, something if we weren't able to see any knockdown in gene expression that we could do a longer study and see some proof of concept efficacy with imaging, specifically MRI or with functional endpoints, things like reachable workspace, we now have that tox coverage at least from the chronic monkey study and I think the chronic rat readout should be available shortly. So we have the ability to design a study that not only could potentially give us biomarker readouts if we're able to measure DUX4 and downstream gene expression, but also a study that would have MRI and functional endpoints built into it as well.

當然。是的，DUX 問題。 DUX4 的表達式是隨機的，這是正確的。因此，肌肉中的蛋白質和受 DUX4 影響的下游基因的測量可能具有挑戰性，正如至少一家其他公司所證明的那樣，這也是原因之一，如果你還記得的話，我們想確保我們有毒素覆蓋範圍以涵蓋更長時間的 II 期研究，如果我們無法看到基因表達的任何敲低，我們可以進行更長時間的研究，並通過成像，特別是 MRI 或功能端點，查看一些概念有效性證明，例如可達工作區，我們現在至少從慢性猴子研究中獲得了毒性覆蓋，我認為慢性大鼠讀數應該很快就會可用。因此，我們有能力設計一項研究，如果我們能夠測量 DUX4 和下游基因表達，不僅可以為我們提供生物標誌物讀數，而且還可以設計一項內置 MRI 和功能終點的研究。

Our next question comes from the line of Prakhar Agrawal of Cantor.

我們的下一個問題來自 Cantor 的 Prakhar Agrawal。

This is Prakhar from Cantor. So first question on ARO-AAT, how long do you think will it take to enroll the Phase III trial, the clinical trial entry for it suggest primary completion date of March 2027 so that would imply roughly 2 years for enrollment. Is that the right proxy to think about the timing of this readout? Or would the timelines be expedited? And I had a quick follow-up.

這是來自 Cantor 的 Prakhar。所以關於 ARO-AAT 的第一個問題，你認為註冊 III 期試驗需要多長時間，它的臨床試驗條目建議主要完成日期為 2027 年 3 月，這意味著大約需要 2 年的註冊時間。這是考慮此讀數時間的正確代理嗎？還是會加快時間表？我有一個快速的跟進。

Yes. I think it's inappropriate for us to opine on that since Takeda will be running that. I think probably best to ask them what their expectations are.

是的。我認為我們對此發表意見是不合適的，因為武田將運行它。我認為最好問問他們的期望是什麼。

Okay. And second on APOC3, any comments on how you're thinking about the trial size and duration for the CV outcomes trial? And what do you think you need to show on the CV outcomes for that asset to have a broad uptake in the patch population?

好的。其次，關於 APOC3，您對 CV 結果試驗的試驗規模和持續時間有何看法？您認為您需要在 CV 結果上顯示什麼才能使該資產在補丁人群中得到廣泛採用？

Yes. Well at the very beginning of that process, as you know, it's not a simple process. We will work with a group of experts, we are at the beginning of establishing the governance on how to design and execute that study. As we said during this call, we are wrapping up the Phase II study within the next quarter or 2 quarters. That will be the way that we will define the study design. We're planning to have interaction with the FDA to talk about that this year. And the expectation is that we will start this study in 2023. So the beginning of the process, a lot of work that needs to be done. Some important decisions that will be related to the specific of the study design, how long they will last. It's likely to be, of course, an event-driven trial as most of these studies are. So a lot to come, a lot to talk about in the next few quarters.

是的。正如你所知，在這個過程的最開始，這不是一個簡單的過程。我們將與一組專家合作，我們正在開始建立關於如何設計和執行該研究的治理。正如我們在本次電話會議中所說，我們將在下一個或兩個季度內完成 II 期研究。這將是我們定義研究設計的方式。我們計劃在今年與 FDA 進行互動來討論這個問題。預計我們將在 2023 年開始這項研究。所以在這個過程的開始，需要做很多工作。一些與研究設計的具體情況相關的重要決定，它們將持續多長時間。當然，這很可能是一項事件驅動的試驗，因為大多數這些研究都是如此。在接下來的幾個季度裡，有很多事情要做，有很多事情要談。

Yes, there are at least a couple of things that are gating for us to figure out what those CVOTs might look like. And one thing is, look, we still haven't read out the entire Phase II studies yet. We have interim analysis that looks quite positive and we're excited about. But we need to finish those studies and see what those look like. That's the first. Second is that we haven't had discussions with the FDA about their expectations. We have to have those. I think once we get through those 2 issues, we'll have -- we can have a better idea about what these things might look like.

是的，至少有幾件事可以讓我們弄清楚這些 CVOT 可能是什麼樣子。一件事是，看，我們還沒有讀完整個 II 期研究。我們的中期分析看起來非常積極，我們對此感到興奮。但我們需要完成這些研究，看看它們是什麼樣子。這是第一個。其次，我們還沒有與 FDA 討論他們的期望。我們必須擁有那些。我認為一旦我們解決了這兩個問題，我們就會——我們可以更好地了解這些事情可能是什麼樣子。

At this time, I'd like to turn the call back over to Dr. Chris Anzalone, President and CEO, for closing remarks. Sir?

此時，我想將電話轉回給總裁兼首席執行官 Chris Anzalone 博士，以作結束語。先生？

Thanks, everyone, for joining us today, and have a nice evening.

謝謝大家今天加入我們，祝大家度過一個愉快的夜晚。

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。