Arrowhead Pharmaceuticals Inc (ARWR) 2023 Q2 法說會逐字稿

Ladies and gentlemen welcome to the Arrowhead Pharmaceuticals conference call. Throughout today's recorded presentation all participants will be in a listen-only mode. After the presentation, there will be an opportunity to ask questions. I will now hand the conference call over to Vincent Anzalone, Vice President of Investor Relations for Arrowhead. Please go-ahead Vince.

女士們，先生們，歡迎參加 Arrowhead Pharmaceuticals 電話會議。在今天錄製的演示文稿中，所有參與者都將處於只聽模式。演示結束後，將有機會提問。我現在將把電話會議交給 Arrowhead 投資者關係副總裁 Vincent Anzalone。請繼續，文斯。

Good afternoon and thank you for joining us today to discuss Arrowhead's results for its fiscal 2023 second quarter ended March 31, 2023.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 & 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.

下午好，感謝您今天加入我們，討論 Arrowhead 截至 2023 年 3 月 31 日的 2023 財年第二季度業績。今天來自管理層的是總裁兼首席執行官 Christopher Anzalone 博士，他將概述本季度；我們的首席醫療官 Javier San Martin 博士將提供我們中後期臨床管道的最新情況；我們的發現與轉化醫學主管 James Hamilton 博士將提供我們早期項目的最新信息；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 和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. For further details concerning these risks and uncertainties, please refer to our SEC filings, including our most recent annual report on Form 10-K and our quarterly reports on Form 10-Q.

在我們開始之前，我想提醒您，在今天的電話會議中發表的評論包含 1933 年證券法第 27A 條和 1934 年證券交易法第 21E 條含義內的某些前瞻性陳述。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。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。

I'd now like to turn the call over to Christopher Anzalone, President and CEO of

我現在想把電話轉給 Christopher Anzalone，總裁兼首席執行官

the Company. Chris?

公司。克里斯？

Thanks Vince. Good afternoon everyone and thank you for joining us today. In 2017, we introduced our proprietary TRiM platform. We believed then that it could become an industry-leading RNAi platform for hepatocyte-focused therapies and, importantly, one that could bring RNAi outside the liver. This was based entirely on our confidence in the potential of the science: at the time we had no clinical programs, a single partner, and our stock was trading for less than $2.

謝謝文斯。大家下午好，感謝您今天加入我們。 2017 年，我們推出了專有的 TRiM 平台。我們當時相信它可以成為行業領先的以肝細胞為中心的療法的 RNAi 平台，更重要的是，它可以將 RNAi 帶到肝臟之外。這完全基於我們對科學潛力的信心：當時我們沒有臨床項目，只有一個合作夥伴，而且我們的股票交易價格不到 2 美元。

Six years later, we have 12 individual drug candidates in clinical studies targeting 2 different organ systems, three ongoing Phase 3 studies, 5 strong partners, a healthy balance sheet, and reason to believe that the next 6 years will be characterized by even more rapid growth.

六年後，我們在針對 2 個不同器官系統的臨床研究中有 12 個個體候選藥物，三個正在進行的 3 期研究，5 個強大的合作夥伴，健康的資產負債表，並且有理由相信未來 6 年的特點是更加快速生長。

We expect to have at least 14 drug candidates in clinical studies by the end of this year, targeting 3 different organ systems: liver, lung, and CNS. Skeletal muscle targeting programs could grow this to 16 individual drug candidates across 4 different organ systems in 2023, but partnering opportunities make that a bit more difficult to predict and I will touch on that later in the call. We are well on our way to reaching our "20 in 25" goal to grow our pipeline of RNAi therapeutics to a total of 20 clinical stage or marketed products in the year 2025. I do not believe there is a company on the planet that will match this.

我們預計到今年年底至少有 14 種候選藥物進入臨床研究，針對 3 個不同的器官系統：肝、肺和中樞神經系統。骨骼肌靶向計劃可能會在 2023 年將其發展為跨越 4 個不同器官系統的 16 種個體候選藥物，但合作機會使其更難以預測，我將在稍後的電話會議中談到這一點。我們正在朝著實現“25 人中有 20 人”的目標邁進，即到 2025 年將我們的 RNAi 療法管線增加到總共 20 種處於臨床階段或已上市的產品。我不相信這個星球上有一家公司會匹配這個。

We've made substantial progress over the past quarter and since our last call. Let's start with pulmonary.

自上次通話以來，我們在過去一個季度取得了實質性進展。讓我們從肺部開始。

We recently disclosed early topline data for ARO-RAGE in normal healthy volunteers. The data were very encouraging and indicated a high level of target gene knockdown with a long duration of effect, in a well-tolerated manner. James will talk about these data in a moment, but I want to put this into context. I believe that Arrowhead is the first company to ever show RNAi mediated target gene knockdown in the lung. Even more impressive was the magnitude of response. We didn't just get on the board, we saw up to 90% knockdown in serum after just two 4 inhaled doses at the 4th of 5 planned dose levels. We do not yet have data from the highest single or multiple dose cohorts. It appears that the pulmonary platform is doing what it was designed to do and ARO-RAGE appears to be highly potent. I expect the durability to enable monthly or less frequent dosing.

我們最近在正常健康志願者中披露了 ARO-RAGE 的早期頂線數據。數據非常鼓舞人心，表明目標基因敲低水平高，效果持續時間長，耐受性良好。詹姆斯稍後會談到這些數據，但我想把它放在上下文中。我相信 Arrowhead 是第一家在肺部顯示 RNAi 介導的靶基因敲除的公司。更令人印象深刻的是反應的幅度。我們不僅加入董事會，而且在 5 個計劃劑量水平中的第 4 個吸入劑量僅兩次 4 次後，我們看到血清中高達 90% 的擊倒。我們還沒有最高單劑量或多劑量隊列的數據。看起來肺部平台正在做它設計要做的事情，ARO-RAGE 似乎非常有效。我希望耐用性能夠實現每月或更少的給藥頻率。

We've often said that clinical validation of the lung platform could mark the beginning of a second rapid wave of growth for our company. Cells don't care what the sequence of an RNAi drug is. Once we find that reducing expression of a specific target gene can be done in a well-tolerated manner, we have a high degree of confidence we can replicate it with any number of new gene targets, much as we have done in the liver. That is where we may be with the pulmonary franchise. I think the data we reported and the additional data we expect to present at the R&D Day on June 1 represent the initial clinical validation we were hoping for. This is a big deal. I fully expect that in the near- to mid-term we will have several potentially important new drug candidates targeting the lung that could address grinding, unmet medical needs.

我們經常說肺平台的臨床驗證可能標誌著我們公司第二波快速增長的開始。細胞不關心 RNAi 藥物的序列是什麼。一旦我們發現可以以耐受性良好的方式降低特定靶基因的表達，我們就有高度的信心可以用任意數量的新基因靶標複製它，就像我們在肝臟中所做的那樣。這就是我們可能與肺特許經營權相關的地方。我認為我們報告的數據以及我們希望在 6 月 1 日的研發日展示的其他數據代表了我們希望獲得的初步臨床驗證。這是一個大問題。我完全預計，在中短期內，我們將有幾種潛在的重要新藥候選藥物靶向肺部，以解決難以滿足的醫療需求。

ARO-MUC5AC will be our next pulmonary data set, and I expect that we will have some normal healthy volunteer data by the R&D Day. These two programs continue to move forward and both have progressed into Part 2 of the Phase 1/2 studies where asthma patients are treated. We hope to have some data from the patient portion of the studies by the end of the year. Rounding out our current pulmonary pipeline is ARO-MMP7. During the last quarter, we initiated a Phase 1/2 study for the treatment of idiopathic pulmonary fibrosis, and we are currently dosing normal healthy volunteers.

ARO-MUC5AC 將是我們的下一個肺部數據集，我希望到研發日我們將獲得一些正常的健康志願者數據。這兩個項目繼續向前推進，都已進入治療哮喘患者的 1/2 期研究的第 2 部分。我們希望在年底之前從研究的患者部分獲得一些數據。完善我們當前的肺管道是 ARO-MMP7。在上個季度，我們啟動了一項治療特發性肺纖維化的 1/2 期研究，目前我們正在對正常的健康志願者進行給藥。

So, where do we go next? The central nervous system. There are a number of untreatable and poorly treated CNS conditions and many genes that could serve as powerful targets for RNAi therapeutics. We have spent a substantial amount of time developing a CNS-focused TRiM platform and are just about ready to bring our first drug candidate to the clinic. As we announced a couple weeks back, ARO-SOD1 is our first CNS-targeted drug candidate to be nominated. It will be investigated as a potential treatment for patients with ALS caused by SOD1 mutations. We have already completed disease model work and CTA enabling toxicology studies and are now on track to file a CTA next quarter. You will hear more about the platform and candidate at the June 1st Analyst Day, and we see these as powerful tools for a new set of patients we seek to serve. Importantly, as with liver, pulmonary, and skeletal muscle delivery, we expect to follow AROSOD1 with several additional drug candidates.

那麼，我們下一步去哪裡？中樞神經系統。有許多無法治療和治療不當的 CNS 疾病和許多基因可以作為 RNAi 治療的強大靶點。我們花費了大量時間開發以 CNS 為中心的 TRiM 平台，並且即將準備好將我們的第一個候選藥物帶到臨床。正如我們幾週前宣布的那樣，ARO-SOD1 是我們第一個被提名的中樞神經系統靶向候選藥物。它將作為 SOD1 突變引起的 ALS 患者的潛在治療方法進行研究。我們已經完成了疾病模型工作和支持毒理學研究的 CTA，現在有望在下個季度提交 CTA。您將在 6 月 1 日的分析師日聽到更多關於該平台和候選人的信息，我們將這些視為我們尋求服務的一組新患者的強大工具。重要的是，與肝臟、肺和骨骼肌的遞送一樣，我們希望在 AROSOD1 之後有幾個額外的候選藥物。

In addition, we have made impressive progress on different modes of administration and while we are not quite there yet, we believe we are approaching the day where we may administer RNAi CNS drug candidates systemically that cross the blood brain barrier. This would be a truly disruptive leap forward and our data suggest that we are close.

此外，我們在不同的管理模式方面取得了令人矚目的進展，雖然我們還沒有完全做到這一點，但我們相信我們正在接近我們可以系統地管理穿過血腦屏障的 RNAi CNS 候選藥物的那一天。這將是真正的顛覆性飛躍，我們的數據表明我們已經接近了。

We look forward to discussing this as well at the Analyst Day. We have said in the past that we are committed to bringing RNAi to where unmet medical need is, and that means constantly expanding TRiM. We believe we can address a new cell type every 18-24 months, and while our new CNS franchise meets this, it is not the only new organ system we are exploring. I believe we can now also deliver to adipose tissue and have demonstrated in non-human primates target gene silencing of greater than 90% with over six months of duration after a single subcutaneous injection, using what we believe are clinically relevant dose levels. Adipose tissue is the largest endocrine organ in the body, and we believe there are many targets to address and many potential patients to help. You will hear more about this new platform next month at the Analyst Day.

我們期待在分析師日討論這個問題。我們過去曾說過，我們致力於將 RNAi 帶到未滿足醫療需求的地方，這意味著不斷擴大 TRiM。我們相信我們可以每 18-24 個月解決一個新的細胞類型，雖然我們新的 CNS 專營權符合這一點，但它並不是我們正在探索的唯一新器官系統。我相信我們現在也可以遞送至脂肪組織，並且已經證明在非人類靈長類動物中，使用我們認為臨床相關的劑量水平，在單次皮下注射後超過 6 個月的持續時間內，靶基因沉默率超過 90%。脂肪組織是體內最大的內分泌器官，我們相信有許多目標需要解決，許多潛在患者需要幫助。您將在下個月的分析師日上聽到有關這個新平台的更多信息。

Let's now turn to our more established clinical programs. We've shared some early data from the Phase 1/2 study of ARO-C3 for complement mediated diseases, and they are compelling. We are seeing deep and durable knockdown in healthy volunteers and have progressed to the patient portion of the study. We also shared liver fat data that Janssen generated in a P1/2 study of ARO-PNPLA3 for NASH in patients with PNPLA3 mutations. Those too were quite encouraging and demonstrated deep reductions in liver fat after only a single dose of ARO-PNPLA3. We plan to move that into a multidose P2 study in NASH patients late this year.

現在讓我們轉向我們更成熟的臨床項目。我們已經分享了 ARO-C3 治療補體介導疾病的 1/2 期研究的一些早期數據，這些數據很有說服力。我們正在健康志願者中看到深度和持久的擊倒，並已進展到研究的患者部分。我們還分享了楊森在 PNPLA3 突變患者 NASH 的 ARO-PNPLA3 P1/2 研究中生成的肝臟脂肪數據。這些也非常令人鼓舞，並且僅在單次劑量的 ARO-PNPLA3 後就顯示出肝臟脂肪的深度減少。我們計劃在今年晚些時候將其納入 NASH 患者的多劑量 P2 研究。

Moving on to our later stage pipeline, we continued to enroll patients in the Phase 3 PALISADE study of ARO-APOC3 in patients with familial chylomicronemia syndrome, or FCS, and expect to meet our enrollment goal of 72 patients tomorrow. There are also some additional patients that have passed screening and who will likely be randomized over the next 2 weeks. At that point enrollment will be complete and I suspect that we will have closer to 80 patients in the study. We also received Fast Track designation from the FDA for ARO-APOC3 for reducing triglycerides in adult patients with FCS, which will be helpful as we advance the program rapidly. Javier will talk about this in a moment, but I expect this to be our first drug to complete a Phase 3 study and, if efficacy and safety are established, could be the first NDA that we file. This could be next year, and it would represent an important step for us. Of course that is not the only population of patients we intend to treat with ARO-APOC3. Rather, I expect us to take steps toward pivotal studies in patients with severe hypertriglyceridemia and those with mixed dyslipidemia later this year.

繼續我們的後期管道，我們繼續在家族性乳糜微粒血症綜合徵或 FCS 患者的 ARO-APOC3 3 期 PALISADE 研究中招募患者，並預計明天將達到 72 名患者的招募目標。還有一些其他患者已通過篩查，並且可能會在接下來的 2 週內隨機分配。屆時登記將完成，我懷疑我們將有近 80 名患者參與研究。我們還獲得了 FDA 對 ARO-APOC3 的快速通道指定，用於降低成年 FCS 患者的甘油三酯，這將有助於我們迅速推進該計劃。 Javier 稍後會談到這一點，但我希望這是我們完成第 3 期研究的第一個藥物，如果確定了療效和安全性，它可能是我們提交的第一個 NDA。這可能是明年，這對我們來說是重要的一步。當然，這並不是我們打算用 ARO-APOC3 治療的唯一患者群體。相反，我希望我們在今年晚些時候採取措施，對嚴重高甘油三酯血症和混合性血脂異常患者進行關鍵研究。

The ARO-ANG3 P2 study in mixed dyslipidemia patients is complete as is the P2 study in patients with homozygous familial hypercholesterolemia, or HoFH. I expect that both of these will move toward P3 studies later this year. Both ARO-ANG3 and ARO-APOC3 appear to be potentially powerful drug candidates. We have included nearly 900 patients in the basket of P2 and P3 studies of ARO-ANG3 and ARO-APOC3 over the past couple of years and continue to be encouraged by the drug candidates' activity and safety profiles. I believe that both of these will ultimately be important drugs for many patients.

混合性血脂異常患者的 ARO-ANG3 P2 研究已經完成，純合子家族性高膽固醇血症或 HoFH 患者的 P2 研究也已完成。我預計這兩項都將在今年晚些時候進入 P3 研究。 ARO-ANG3 和 ARO-APOC3 似乎都是潛在的強大候選藥物。在過去的幾年裡，我們將近 900 名患者納入了 ARO-ANG3 和 ARO-APOC3 的 P2 和 P3 研究籃子中，並繼續受到候選藥物的活性和安全性的鼓舞。我相信這兩者最終都會成為很多患者的重要藥物。

Also, during the quarter, we announced that our partner Takeda had treated the first patient in the Phase 3 REDWOOD study of fazirsiran being investigated as a potential treatment for alpha-1 antitrypsin deficiency liver disease. This is the third TRiM enabled candidate to reach a Phase 3 study, which earned Arrowhead a $40 million milestone payment.

此外，在本季度，我們宣布我們的合作夥伴 Takeda 已經治療了 fazirsiran 的第 3 期 REDWOOD 研究中的第一位患者，該研究被調查為 alpha-1 抗胰蛋白酶缺乏性肝病的潛在治療方法。這是第三個啟用 TRiM 的候選藥物進入第三階段研究，Arrowhead 獲得了 4000 萬美元的里程碑付款。

We also received a $30 million milestone payment from GSK after the start of GSK's Phase 2b trial of GSK4532990, formerly called ARO-HSD, an investigational RNAi therapeutic for the treatment of patients with NASH. These milestone payments are helpful for our balance sheet but also represent two more important things. First, they are a confirmation that our strategy to have a healthy mix of both wholly owned and partnered programs is playing out as intended. Second, they indicate that important new medicines that Arrowhead discovered are getting closer to the patients that need them.

在 GSK 的 GSK4532990 的 2b 期試驗開始後，我們還收到了來自 GSK 的 3000 萬美元里程碑付款，GSK4532990 以前稱為 ARO-HSD，是一種用於治療 NASH 患者的研究性 RNAi 療法。這些里程碑付款對我們的資產負債表有幫助，但也代表了兩件更重要的事情。首先，它們證實了我們將全資和合作項目健康組合的戰略正在按預期發揮作用。其次，它們表明 Arrowhead 發現的重要新藥越來越接近需要它們的患者。

Before I hand off to Javier, let me say a few words about the skeletal muscle franchise and ARO-DUX4 specifically. We completed everything required for the CTA including regulatory filing preparation, acute and even chronic GLP toxicology studies. We are prepared to file the CTA and begin a P1/2 study but several companies have expressed interest in potentially partnering on the development of ARO-DUX4 and, potentially, our next skeletal muscle-targeted drug candidate, that will be CTA-ready in Q4. As such, we paused filing while we explore these options. Of course, I do not know if any of these will translate into license agreements and partnerships, but I expect we will either complete a deal or move forward with the ARO-DUX4 clinical program over the next couple months.

在我交給 Javier 之前，讓我先簡單介紹一下骨骼肌專營權和 ARO-DUX4。我們完成了 CTA 所需的一切，包括監管備案準備、急性甚至慢性 GLP 毒理學研究。我們準備提交 CTA 並開始 P1/2 研究，但有幾家公司表示有興趣合作開發 ARO-DUX4，並且有可能是我們的下一個骨骼肌靶向候選藥物，它將在Q4.因此，我們在探索這些選項時暫停了提交。當然，我不知道這些是否會轉化為許可協議和合作夥伴關係，但我預計我們將在未來幾個月內完成交易或推進 ARO-DUX4 臨床計劃。

Arrowhead is executing at a very high level: our platform is expanding into new areas; our early pipeline is generating impressive results; our mid and later stage pipeline are giving us line of sight to when we may be able to make the transition into a commercial stage company; and our business development activities continue to bear fruit.

Arrowhead 的執行水平非常高：我們的平台正在擴展到新的領域；我們早期的管道正在產生令人印象深刻的結果；我們的中後期管道讓我們看到了何時可以過渡到商業階段的公司；我們的業務發展活動繼續取得成果。

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

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

Javier?

哈維爾？

Thank you, Chris, and good afternoon everyone. Before I go into the mid and late stage cardiometabolic studies, I want to quickly review the status of the fazirsiran, our investigational RNAi therapeutic being developed in partnership with Takeda for the treatment of liver disease associated with alpha-1 antitrypsin deficiency.

謝謝克里斯，大家下午好。在我進入中期和晚期心臟代謝研究之前，我想快速回顧一下 fazirsiran 的狀態，這是我們與武田合作開發的研究性 RNAi 治療藥物，用於治療與 alpha-1 抗胰蛋白酶缺乏症相關的肝病。

During the last quarter we reported data demonstrating that patients receiving 25, 100, or 200 mg of fazirsiran who had baseline fibrosis achieved a dose dependent mean reduction in serum Z-AAT concentration at week 48 of 74%, 89%, and 94%, respectively, leading to dramatic reductions in total liver Z-AAT and PAS-D globule burden, a histological measure of Z-AAT accumulation. In addition 42% of patients showed an improvement in portal inflammation and 50% of patients achieved an improvement in fibrosis of at least one point by METAVIR stage.

在上個季度，我們報告的數據表明，接受 25、100 或 200 毫克 fazirsiran 的基線纖維化患者在第 48 週時血清 Z-AAT 濃度的劑量依賴性平均降低 74%、89% 和 94%，分別導致肝臟總 Z-AAT 和 PAS-D 球負荷顯著降低，這是 Z-AAT 積累的組織學測量。此外，42% 的患者表現出門靜脈炎症有所改善，50% 的患者在 METAVIR 階段的纖維化方面至少有一個點的改善。

These data were very consistent with the prior data generated from the 2002 open label study. Subsequently, Takeda initiated and began dosing in the REDWOOD clinical study. It is a randomized, double-blind, placebo-controlled, Phase 3 trial to evaluate the efficacy and safety of fazirsiran in the treatment of AATD liver disease. Approximately 160 adult patients with METAVIR stage F2 to F4 fibrosis will be randomized 1:1 to receive fazirsiran or placebo. The primary endpoint of the study is a decrease from baseline of at least 1 stage of histologic fibrosis METAVIR staging in the centrally read liver biopsy done at Week 106 in patients with METAVIR stage F2 and F3 fibrosis. Additional information on the REDWOOD study can be found at www.theredwoodliverstudy.com. I also want to give a brief update on where we are with our cardiometabolic candidates, ARO-APOC3 and ARO-ANG3.

這些數據與 2002 年開放標籤研究生成的先前數據非常一致。隨後，武田在 REDWOOD 臨床研究中發起並開始給藥。這是一項隨機、雙盲、安慰劑對照的 3 期試驗，旨在評估 fazirsiran 治療 AATD 肝病的療效和安全性。大約 160 名患有 METAVIR F2 至 F4 期纖維化的成年患者將按照 1:1 的比例隨機分配接受法齊西蘭或安慰劑。該研究的主要終點是在第 106 週對 METAVIR F2 和 F3 期纖維化患者進行的集中讀取肝活檢中，組織學纖維化 METAVIR 分期的至少 1 個階段從基線下降。有關 REDWOOD 研究的更多信息，請訪問 www.theredwoodliverstudy.com。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。

I will start with ARO-APOC3, our investigational RNAi therapeutic being developed as a treatment for patients with mixed dyslipidemia, severe hypertriglyceridemia, and FCS. The SHASTA-2 Phase 2 study in 229 patients with severe hypertriglyceridemia and the MUIR Phase 2 study in 353 patients with mixed dyslipidemia are both on schedule for data readouts later this year. These data will enable us to request end of Phase 2 meetings with regulators to discuss and get feedback on our plans for Phase 3 studies.

我將從 ARO-APOC3 開始，這是我們正在開發的研究性 RNAi 療法，用於治療患有混合性血脂異常、嚴重高甘油三酯血症和 FCS 的患者。對 229 名嚴重高甘油三酯血症患者進行的 SHASTA-2 2 期研究和對 353 名混合性血脂異常患者進行的 MUIR 2 期研究均按計劃在今年晚些時候公佈數據。這些數據將使我們能夠要求結束與監管機構的第 2 階段會議，以討論我們的第 3 階段研究計劃並獲得反饋。

The PALISADE Phase 3 study in 72 patients with FCS is ongoing. We have enrolled 70 of the planned 72 patients and we believe we will reach planned enrollment tomorrow. This is a 48 week study with a primary endpoint of percent change from baseline in fasting triglycerides. This puts us on schedule for study completion in Q2 of 2024, a data readout shortly after that, and then NDA preparation. I am also pleased to announce that during last quarter ARO-APOC3 was granted Fast Track designation by the US FDA for reducing triglycerides in adult patients with FCS. ARO-APOC3 was previously granted Orphan Drug designation by the FDA and the European Union for the same use.

對 72 名 FCS 患者進行的 PALISADE 3 期研究正在進行中。我們已經招募了 72 名計劃的 72 名患者中的 70 名，我們相信明天我們將達到計劃的招募人數。這是一項為期 48 週的研究，其主要終點是空腹甘油三酯相對於基線的百分比變化。這使我們按計劃在 2024 年第二季度完成研究，之後不久將讀取數據，然後準備 NDA。我也很高興地宣布，在上個季度，ARO-APOC3 被美國 FDA 授予快速通道指定，用於降低成年 FCS 患者的甘油三酯。 ARO-APOC3先前被 FDA 和歐盟授予孤兒藥資格，用於相同用途。

Fast Track is a process designed to expedite the development and review of drugs to treat serious or life-threatening conditions and fulfill an unmet medical need. The purpose is to get important new drugs to patients earlier. This designation makes Arrowhead eligible for multiple potential benefits including more frequent interactions with FDA, eligibility for priority review, and eligibility for rolling review of the NDA. Once we have complete data from the Phase 3 PALISADE study in 2024, we intend to utilize all available mechanisms to get this potentially important drug to patients as quickly as possible. This would be the first Phase 3 readout for Arrowhead and our pipeline of RNAi therapeutics that utilize our proprietary TRiM platform. That represents a significant milestone for the company.

Fast Track 是一個旨在加快藥物開發和審查以治療嚴重或危及生命的疾病並滿足未滿足的醫療需求的過程。目的是讓重要的新藥更早地送到患者手中。這一指定使 Arrowhead 有資格獲得多項潛在利益，包括與 FDA 更頻繁的互動、優先審查的資格以及 NDA 滾動審查的資格。一旦我們在 2024 年獲得 3 期 PALISADE 研究的完整數據，我們打算利用所有可用機制盡快將這種潛在重要的藥物提供給患者。這將是 Arrowhead 和我們利用我們專有的 TRiM 平台的 RNAi 療法管道的第一個第 3 階段讀數。這對公司來說是一個重要的里程碑。

Moving on to the second wholly-owned cardiometabolic candidate ARO-ANG3, which is our investigational RNAi therapeutic being developed as a treatment for homozygous familial hypercholesterolemia, or HoFH, and heterozygous familial hypercholesterolemia, or HeFH. We have completed the ARCHES-2 Phase 2 study in 204 patients with mixed dyslipidemia and we are currently in the process of generating and analyzing study data, which we intend to report on later this year. The second Phase 2 study of ARO-ANG3 is the GATEWAY study in 18 patients with HoFH. This study is open label and was fully enrolled previously. I'm happy to report that the LDL-C reduction in this difficult to treat population with limited treatment options appears to be competitive with evinacumab, a monoclonal antibody that targets the same ANGPTL3 protein which is currently approved for HoFH patients. We will present interim data for the GATEWAY study at the 91st European Atherosclerosis Society Congress on May 23. These were welcome results, and thus we are currently working on a Phase 3 study design and plan for ARO-ANG3 in HoFH.

接下來是第二個全資擁有的心臟代謝候選藥物 ARO-ANG3，這是我們正在開發的研究性 RNAi 治療藥物，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。我們已經完成了對 204 名混合性血脂異常患者的 ARCHES-2 2 期研究，我們目前正在生成和分析研究數據，我們打算在今年晚些時候報告這些數據。 ARO-ANG3的第二個2期研究是對18名HoFH患者進行的GATEWAY研究。這項研究是開放標籤的，之前已完全註冊。我很高興地報告，在這個治療選擇有限且難以治療的人群中，LDL-C 的降低似乎與 evinacumab 具有競爭力，evinacumab 是一種靶向相同 ANGPTL3 蛋白的單克隆抗體，目前已批准用於 HoFH 患者。我們將在 5 月 23 日舉行的第 91 屆歐洲動脈粥樣硬化學會大會上展示 GATEWAY 研究的中期數據。這些結果令人欣喜，因此我們目前正在 HoFH 進行 ARO-ANG3 的 3 期研究設計和計劃。

We will also talk in more detail about the unmet need in cardiovascular disease, the results from our cardiometabolic programs, our clinical development plans, and our commercial strategy at the upcoming R&D Day in June.

我們還將在 6 月即將到來的研發日更詳細地討論心血管疾病方面未滿足的需求、我們心臟代謝項目的結果、我們的臨床開發計劃以及我們的商業戰略。

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 have demonstrated significant progress across discovery and early development. We continue to extend the reach of our TRiM platform to new tissue types and expand our pipeline into new disease areas in which patients have inadequate treatment options. We have also rapidly and efficiently advanced multiple early clinical stage programs and continue to generate highly encouraging data using various versions of the TRiM platform, each optimized for a different cell type.

謝謝你，哈維爾。我們已經在發現和早期開發方面取得了重大進展。我們繼續將 TRiM 平台的範圍擴展到新的組織類型，並將我們的產品線擴展到患者沒有足夠治療選擇的新疾病領域。我們還快速有效地推進了多個早期臨床階段項目，並繼續使用各種版本的 TRiM 平台生成非常鼓舞人心的數據，每個版本都針對不同的細胞類型進行了優化。

I want to focus today on a few different areas: The pulmonary platform, with recent topline data announced for ARO-RAGE; ARO-C3, our candidate for complement mediated diseases; and, our emerging CNS platform, with the first candidate being ARO-SOD1.

我今天想重點關注幾個不同的領域： 肺部平台，最近公佈了 ARO-RAGE 的頂線數據； ARO-C3，我們的補體介導疾病候選藥物；以及我們新興的 CNS 平台，第一個候選平台是 ARO-SOD1。

Let's start with pulmonary. We have three candidates in the clinic now: ARORAGE, ARO-MUC5AC, and ARO-MMP7, which all use the same TRiM conjugate that targets the αvβ6 integrin for delivery to pulmonary epithelial cells. I will talk about each individually, but we think one of the benefits of gaining a RNAi therapeutic delivery platform with increasing validation is that learnings from each program can directly inform advancements in others. So, we view derisking events for one program, such as the data we saw with ARO-RAGE, as potentially de-risking to some extent to the others.

讓我們從肺部開始。我們現在在臨床上有三個候選藥物：ARORAGE、ARO-MUC5AC 和 ARO-MMP7，它們都使用相同的 TRiM 偶聯物，靶向 αvβ6 整合素以遞送至肺上皮細胞。我將分別討論每個項目，但我們認為獲得 RNAi 治療交付平台並獲得越來越多的驗證的好處之一是，從每個項目中學習可以直接為其他項目的進步提供信息。因此，我們認為一個程序的去風險事件，例如我們在 ARO-RAGE 中看到的數據，在某種程度上可能會降低其他程序的風險。

ARO-RAGE is our investigational RNAi therapeutic designed to reduce expression of the receptor for advanced glycation end products, or RAGE, as a potential treatment for inflammatory pulmonary diseases, such as asthma. We are currently conducting a Phase 1/2a, randomized, double-blinded, placebo-controlled study in normal healthy volunteers, which is Part 1, and in patients with mild-to-moderate asthma, which is Part 2. The single ascending dose portion of the study includes 5 sequentially enrolled NHV cohorts with escalating single-dose levels. The multiple ascending dose portion of the study includes 5 NHV cohorts and 3 asthma patient cohorts.

ARO-RAGE 是我們的研究性 RNAi 治療藥物，旨在減少晚期糖基化終產物受體或 RAGE 的表達，作為炎症性肺病（如哮喘）的潛在治療方法。我們目前正在正常健康志願者（第 1 部分）和輕度至中度哮喘患者（第 2 部分）中進行一項 1/2a 期、隨機、雙盲、安慰劑對照研究。單次遞增劑量該研究的一部分包括 5 個按順序登記的 NHV 隊列，其單劑量水平不斷上升。該研究的多次遞增劑量部分包括 5 個 NHV 隊列和 3 個哮喘患者隊列。

We have fully enrolled and dosed all SAD cohorts and the final MAD cohort is anticipated to be fully enrolled in the coming weeks. We have also opened the patient cohorts with enrollment of the first cohort nearly complete. We reported very encouraging topline results from 4 of the 5 SAD and MAD

我們已經對所有 SAD 隊列進行了全面招募和給藥，最終的 MAD 隊列預計將在未來幾週內完成招募。我們還開放了患者隊列，第一批隊列的註冊工作已接近完成。我們報告了 5 個 SAD 和 MAD 中的 4 個非常令人鼓舞的頂線結果

cohorts in NHVs. We do not yet have data from the 5th and highest dose level, but we plan to report on those results when they are available later this year.

NHV 中的隊列。我們還沒有第 5 個和最高劑量水平的數據，但我們計劃在今年晚些時候獲得這些結果時報告這些結果。

First, safety and tolerability assessments have been encouraging. Overall, there were no patterns of adverse changes in any clinical safety parameters, no reported serious or severe adverse events, and no dropouts related to drug or related to adverse events.

首先，安全性和耐受性評估一直令人鼓舞。總的來說，沒有任何臨床安全參數的不良變化模式，沒有報告嚴重或嚴重的不良事件，也沒有與藥物或不良事件相關的輟學。

In addition to safety and tolerability, ARO-RAGE demonstrated a strong pharmacodynamic effect. The mean maximum reduction in soluble RAGE, or sRAGE, at the 92 mg dose as measured in serum after two doses on Day 1 and Day 29 was 80% with a maximum reduction of 90%. The lower doses of 10, 20, and 44 mg also showed a dose response ranging from 31% to 59%. Serum sRAGE was also reduced after a single dose, with a mean maximum reduction at the 92 mg dose of 56% and a maximum reduction of 68%. Reductions in sRAGE as measured in bronchoalveolar lavage fluid on Day 31 after a single dose were also observed, with a mean reduction at 92 mg of 75% and a maximum reduction of 92%. We have additional planned cohorts in which BALF will be collected at later timepoints to quantify the additional lung level knockdown after two doses.

除了安全性和耐受性，ARO-RAGE 還表現出強大的藥效學作用。在第 1 天和第 29 天兩次給藥後在血清中測量的 92 mg 劑量下可溶性 RAGE 或 sRAGE 的平均最大減少為 80%，最大減少為 90%。 10、20 和 44 毫克的較低劑量也顯示出 31% 至 59% 的劑量反應。單次給藥後血清 sRAGE 也降低，在 92 mg 劑量時平均最大降低 56%，最大降低 68%。還觀察到在單次給藥後第 31 天在支氣管肺泡灌洗液中測量的 sRAGE 減少，在 92 mg 時平均減少 75%，最大減少 92%。我們有額外的計劃隊列，其中將在稍後的時間點收集 BALF，以量化兩次劑量後額外的肺水平擊倒。

Lastly, the duration of pharmacologic effect persisted for at least 6 weeks after the second administration of the 92 mg dose. This is the last timepoint currently available and additional follow up is ongoing. This suggests that monthly, bimonthly, or less frequent dosing may be possible with ARO-RAGE. All in all, we believe these data show good translation of preclinical results to humans. Moving on to ARO-MUC5AC, our investigational RNAi therapeutic designed to reduce production of mucin 5AC, or MUC5AC, as a potential treatment for various muco-obstructive pulmonary diseases. We are currently conducting a Phase 1/2a study, similar in design to the ARO-RAGE study and we have begun enrollment of the asthma patient cohorts.

最後，藥理作用的持續時間在第二次給予 92 mg 劑量後至少持續 6 週。這是目前可用的最後一個時間點，並且正在進行其他跟進。這表明 ARO-RAGE 可能每月、每兩個月或更不頻繁地給藥。總而言之，我們相信這些數據顯示了臨床前結果對人類的良好轉化。接下來是 ARO-MUC5AC，我們的研究性 RNAi 療法旨在減少粘蛋白 5AC 或 MUC5AC 的產生，作為各種粘液阻塞性肺病的潛在治療方法。我們目前正在進行一項 1/2a 期研究，其設計類似於 ARO-RAGE 研究，我們已經開始招募哮喘患者隊列。

Sample processing and analysis for the NHV cohorts is ongoing and we intend to report on initial data when available. The third pulmonary program in the clinic is ARO-MMP7, which is designed to reduce expression of matrix metalloproteinase 7, or MMP7, as a potential treatment for idiopathic pulmonary fibrosis, or IPF. During the last quarter we initiated a Phase 1/2a single ascending dose and multiple ascending dose study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of ARO-MMP7 in healthy volunteers and patients with IPF. Dose escalation in this study is ongoing.

NHV 隊列的樣本處理和分析正在進行中，我們打算在可用時報告初始數據。臨床中的第三個肺部項目是 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。在上個季度，我們啟動了一項 1/2a 期單次遞增劑量和多次遞增劑量研究，以評估 ARO-MMP7 在健康志願者和 IPF 患者中的安全性、耐受性、藥代動力學和藥效學。本研究中的劑量遞增正在進行中。

Now let's discuss initial results with ARO-C3, our investigational RNAi therapeutic targeting hepatic C3 expression as a potential treatment for complement mediated hematologic and renal diseases. Substantial unmet medical need remains in the treatment of multiple complement mediated diseases, including IgA nephropathy, C3 glomerulopathy, and additional renal and hematologic indications.

現在讓我們討論 ARO-C3 的初步結果，我們的研究性 RNAi 治療靶向肝 C3 表達，作為補體介導的血液和腎臟疾病的潛在治療方法。在治療多種補體介導的疾病方面仍然存在大量未滿足的醫療需求，包括 IgA 腎病、C3 腎小球病以及其他腎臟和血液學適應症。

We are conducting a Phase 1/2, placebo controlled, dose-escalating study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of ARO-C3 in adult healthy volunteers and patients with complement-mediated renal disease. We originally planned to also include patients with PNH in this study, but we have since decided to eliminate these cohorts. We may decide to study PNH patients in the future, but we believe we can generate the data we need in the other populations. During the quarter we reported topline interim data and presented additional data at the 7th Complement UK Training Course and Symposium in April. In Part 1 of the study in NHVs, ARO-C3 demonstrated a dose-dependent reduction in serum C3, with 88% mean reduction after two doses at highest dose tested. A dose-dependent reduction in AH50, a marker of alternative complement pathway hemolytic activity, was also observed with a 91% mean reduction at highest dose tested. ARO-C3 had a long duration of pharmacologic effect, and we think this suggests quarterly or less frequent subcutaneous dose administration is possible.

我們正在進行一項 1/2 期、安慰劑對照、劑量遞增的研究，以評估 ARO-C3 在成年健康志願者和補體介導的腎病患者中的安全性、耐受性、藥代動力學和藥效學。我們最初計劃在這項研究中也包括 PNH 患者，但我們已經決定消除這些隊列。我們可能會決定在未來研究 PNH 患者，但我們相信我們可以在其他人群中生成我們需要的數據。在本季度，我們報告了頂線中期數據，並在 4 月舉行的第 7 屆英國補充培訓課程和研討會上展示了更多數據。在 NHVs 研究的第 1 部分中，ARO-C3 證明了血清 C3 的劑量依賴性降低，在測試的最高劑量下兩次給藥後平均降低 88%。還觀察到 AH50 的劑量依賴性降低，AH50 是替代補體途徑溶血活性的標誌物，在最高測試劑量下平均降低 91%。 ARO-C3 的藥理作用持續時間長，我們認為這表明每季度一次或更低頻率的皮下給藥是可能的。

Lastly, I want to briefly mention our announcement that CNS is the next area of focus for the TRiM platform. We have been working on CNS delivery for some time but have not discussed these efforts publicly until now. Our TRiM platform now includes a construct optimized for intrathecal administration to the central nervous system with good distribution throughout the brain and in all relevant brain cell types.

最後，我想簡單提一下我們宣布 CNS 是 TRiM 平台的下一個重點領域。我們致力於 CNS 交付已有一段時間，但直到現在才公開討論這些努力。我們的 TRiM 平台現在包括一個針對中樞神經系統鞘內給藥優化的結構，在整個大腦和所有相關腦細胞類型中分佈良好。

ARO-SOD1, the first program to use this new delivery platform, is designed to reduce expression of superoxide dismutase 1, or SOD1, in the CNS as a potential treatment for patients with amyotrophic lateral sclerosis, or ALS, caused by SOD1 mutations. ARO-SOD1 was highly active against its target with a long duration of effect in multiple preclinical models that we believe suggests it may be administered quarterly or less frequently. In preclinical studies, ARO-SOD1 achieved 95% spinal cord tissue mRNA knockdown after a single intrathecal dose in SOD1 transgenic rats and maintained greater than 80% spinal cord tissue mRNA knockdown three months after a single intrathecal dose in non-human primates.

ARO-SOD1是第一個使用這種新遞送平台的項目，旨在減少中樞神經系統中超氧化物歧化酶1（SOD1）的表達，作為由 SOD1 突變引起的肌萎縮側索硬化症（ALS）患者的潛在治療方法。 ARO-SOD1 對其靶標具有高度活性，在多個臨床前模型中效果持續時間長，我們認為這表明它可能每季度或更低頻率給藥。在臨床前研究中，ARO-SOD1 在 SOD1 轉基因大鼠中單次鞘內給藥後實現了 95% 的脊髓組織 mRNA 敲低，在非人靈長類動物中單次鞘內給藥後三個月後脊髓組織 mRNA 的敲低保持在 80% 以上。

ARO-SOD1, is on track for a CTA filing in the third quarter of 2023. We will talk more about our CNS platform and about ARO-SOD1 at the R&D Day in June, but I wanted to introduce the program because we are very excited about the potential for siRNA in the CNS.

ARO-SOD1 有望在 2023 年第三季度提交 CTA 申請。我們將在 6 月的研發日更多地討論我們的 CNS 平台和 ARO-SOD1，但我想介紹這個項目，因為我們非常興奮關於 siRNA 在 CNS 中的潛力。

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

我現在將把電話轉給 Ken Myszkowski。肯？

Ken Myszkowski Thank you, James, and good afternoon, everyone. As we reported today, our net income for the quarter ended March 31, 2023 was $48.7 million or $0.45 per share based on 108.1 million fully-diluted weighted average shares outstanding. This compares with net income of $44.4 million or $0.41 per share based on 107.9 million fully-diluted weighted average shares outstanding, for the quarter ended March 31, 2022. Revenue for the quarter ended March 31, 2023 was 146.3 million, compared to 151.8 million for the quarter ended March 31, 2022. Revenue in the current period primarily relates to our collaboration agreements with Takeda and GSK.

Ken Myszkowski 謝謝 James，大家下午好。正如我們今天報導的那樣，我們截至 2023 年 3 月 31 日的季度淨收入為 4870 萬美元或每股 0.45 美元，基於 1.081 億股完全稀釋的加權平均流通股。相比之下，截至 2022 年 3 月 31 日止季度的淨收入為 4440 萬美元或每股 0.41 美元，基於 1.079 億股完全稀釋加權平均流通股。截至 2023 年 3 月 31 日止季度的收入為 1.463 億美元，而 1.518 億美元截至 2022 年 3 月 31 日的季度。本期收入主要與我們與武田和葛蘭素史克的合作協議有關。

Revenue is recognized as we complete our performance obligations, which include managing the ongoing AAT Phase 2 clinical trials for Takeda. There remains $31 million of revenue to be recognized associated with the Takeda collaboration which we anticipate will be recognized over the next year. Additionally in the quarter ended March 31, 2023, Takeda dosed the first patient in its Phase 3 REDWOOD clinical study of fazirsiran, triggering a $40.0 million milestone payment, and GSK dosed the first patient in its Phase 2b trial of GSK4532990, formerly known as ARO-HSD, in March, triggering a $30.0 million milestone payment. Both milestone payments are expected to be paid in the third quarter of fiscal 2023. Revenue in the prior period primarily related to the recognition of the $120.0 million associated with the upfront payment received from GSK in addition to a portion of the payments received from our license and collaboration agreements with Takeda and Horizon. Total operating expenses for the quarter ended March 31, 2023 were $98.1 million, compared to $110.3 million for the quarter ended March 31, 2022. The key driver of this change was decreased candidate costs and lower stock compensation expense. The decreased candidate costs were primarily due to the reduction in outsourced manufacturing and toxicity study costs related to our cardiometabolic studies as the Company's pipeline of candidates progressed through clinical trials in 2022.

收入在我們完成履約義務時確認，其中包括管理武田正在進行的 AAT 2 期臨床試驗。與武田合作相關的收入仍有 3100 萬美元需要確認，我們預計這將在明年確認。此外，在截至 2023 年 3 月 31 日的季度中，武田 (Takeda) 在其 fazirsiran 的 3 期 REDWOOD 臨床研究中為第一位患者給藥，觸發了 4000 萬美元的里程碑付款，而葛蘭素史克 (GSK) 在其 2b 期試驗 GSK4532990（前身為 ARO）中為第一位患者給藥-HSD，3 月，觸發了 3000 萬美元的里程碑付款。兩項里程碑付款預計將在 2023 財年第三季度支付。前期收入主要與確認與從 GSK 收到的預付款相關的 1.2 億美元以及從我們的許可收到的部分付款有關以及與武田和地平線的合作協議。截至 2023 年 3 月 31 日的季度總運營費用為 9810 萬美元，而截至 2022 年 3 月 31 日的季度為 1.103 億美元。這一變化的主要驅動因素是候選人成本的降低和股票補償費用的降低。候選藥物成本的下降主要是由於與我們的心臟代謝研究相關的外包製造和毒性研究成本的減少，因為公司的候選藥物管道在 2022 年通過了臨床試驗。

Net cash used by operating activities during the quarter ended March 31, 2023 was $107.2 million, compared with net cash provided by operating activities of $1.4 million for the quarter ended March 31, 2022. The prior period includes $120 million cash inflow from the GSK licensing and collaboration agreement. We expect our operating cash burn to be at the lower range of $70 to $90 million per quarter in fiscal 2023. We expect capital expenditures of approximately $90 million in the second half of fiscal 2023 as we near completion on our footprint expansion projects, including GMP manufacturing.

截至 2023 年 3 月 31 日的季度，經營活動使用的現金淨額為 1.072 億美元，而截至 2022 年 3 月 31 日的季度，經營活動提供的現金淨額為 140 萬美元。上一期間包括來自 GSK 許可的 1.2 億美元現金流入和合作協議。我們預計 2023 財年我們的運營現金消耗將在每季度 70 至 9000 萬美元的較低範圍內。隨著我們即將完成包括 GMP 在內的足跡擴張項目，我們預計 2023 財年下半年的資本支出約為 9000 萬美元製造業。

Turning to our balance sheet, our cash and investments totaled 559.8 million at March 31, 2023, compared to $482.3 million at September 30, 2022. The increase in our cash and investments was primarily related to the $250.0 million payment from Royalty Pharma, offset by our operating cash burn along with continuing capital projects. Our common shares outstanding at March 31, 2023, were 106.9 million. With that brief overview, I will now turn the call back to Chris.

轉向我們的資產負債表，我們的現金和投資在 2023 年 3 月 31 日總計 5.598 億美元，而在 2022 年 9 月 30 日為 4.823 億美元。我們的現金和投資的增加主要與來自 Royalty Pharma 的 2.50 億美元付款有關，被我們的運營現金與持續的資本項目一起燃燒。截至 2023 年 3 月 31 日，我們的已發行普通股為 1.069 億股。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 have already had a busy 2023 and have made a great deal of progress on many fronts. However, we anticipate that the middle and into the second half of the year will be even busier and offer even more opportunities to demonstrate what our pipeline can bring to patients.

謝謝肯。我們已經度過了忙碌的 2023 年，並在許多方面取得了很大進展。然而，我們預計今年中期和下半年將更加繁忙，並提供更多機會來展示我們的管道可以為患者帶來什麼。

We have always been clear that we believe for RNAi to reach its full potential as a revolutionary therapeutic modality, it needs to be able to address gene targets wherever they are. That no longer feels like a long-term goal. Between the liver franchise, the pulmonary franchise, the skeletal muscle franchise, the CNS franchise, and the adipose franchise, we have the opportunity to help a lot of people and create a substantial amount of value. But this is just the start. I expect us to blow through 20 in '25 and build a uniquely large and diverse pipeline of important medicines across multiple therapeutic areas. I have never been more excited about our near-term prospects or more proud of this amazing team. When you combine a technology that works with talented innovators who are aligned as to mission and empowered to make decisions and push science, incredible things can follow. We hope you can all join us on June 1 at our R&D Day to hear more. Thank you for joining us today and I would now like to open the call to your questions. Operator?

我們一直很清楚，我們相信 RNAi 作為一種革命性的治療方式要發揮其全部潛力，它需要能夠解決任何地方的基因靶點。這不再是一個長期目標。在肝臟專營權、肺部專營權、骨骼肌專營權、CNS 專營權和脂肪專營權之間，我們有機會幫助很多人並創造大量價值。但這僅僅是開始。我希望我們能夠在 25 年突破 20 年，並在多個治療領域建立一個獨特的龐大而多樣化的重要藥物管道。我從未對我們的近期前景感到如此興奮，也從未為這支出色的團隊感到如此自豪。當您將一項技術與有才華的創新者結合起來，這些創新者在使命上保持一致並有權做出決策和推動科學發展時，不可思議的事情就會隨之而來。我們希望你們都能在 6 月 1 日的研發日加入我們，了解更多信息。感謝您今天加入我們，我現在想開始回答您的問題。操作員？

Thank you all. (Operator Instructions).

謝謝你們。 （操作員說明）。

I also want to just remind analysts that we – in the interest of time, we like to limit the questions to one question and one follow-up.

我還想提醒分析師們，我們——為了節省時間，我們希望將問題限制為一個問題和一個後續行動。

Alright. Our first question comes from the line of Maury Raycroft with Jefferies.

好吧。我們的第一個問題來自 Maury Raycroft 與 Jefferies 的合作。

I was going to ask if you can provide some additional detail on what new data we see at the R&D day from the cardiometabolic and pulmonary program specifically? And as follow-up for the Phase 3 PALISADE study, you mentioned readout in second quarter 2024, I'm just wondering if you will report on patient baseline characteristics at the R&D day or potentially at a medical meeting this year?

我想問你是否可以提供一些額外的細節，具體說明我們在研發日從心臟代謝和肺部項目中看到了哪些新數據？作為 3 期 PALISADE 研究的後續行動，你提到了 2024 年第二季度的讀數，我只是想知道你是否會在研發日或可能在今年的醫學會議上報告患者基線特徵？

Thanks, Maury. So there's – I think, there's different questions there. What are we going to be talking about the R&D day? We'll be overviewing the pulmonary programs of course and we'll give you what data we will have at the time. We expect, as I mentioned in the prepared remarks, we expect to have some early non-healthy volunteer data from MUC5AC. I don't expect that we'll have MMB7 data, but we'll – we'll also likely have a bit more of ARO-RAGE.

謝謝，莫里。所以 - 我認為，那裡有不同的問題。我們將在研發日談論什麼？當然，我們將概述肺部項目，屆時我們將為您提供我們將擁有的數據。正如我在準備好的評論中提到的，我們希望從 MUC5AC 獲得一些早期的非健康志願者數據。我不希望我們會有 MMB7 數據，但我們會——我們也可能會有更多的 ARO-RAGE。

We also – we will talk about those indications or those targets, as well as the indications. On the cardiometabolic side, it'll be a good chance for us to talk broadly about how we see ARO-ANG3 and ARO-APOC3 fitting into treatment paradigms. We'll talk a bit about a more recent data as well. We'll talk about the new CNS platform. We'll probably go into a little bit of the adipose platform a bit. We'll talk about SOD1, we'll talk about the portion of ALS that we'll be addressing with SOD1.

我們也 - 我們將討論這些跡像或目標，以及跡象。在心臟代謝方面，這將是我們廣泛討論我們如何看待 ARO-ANG3 和 ARO-APOC3 適合治療範式的好機會。我們還將討論一些最近的數據。我們將討論新的 CNS 平台。我們可能會稍微介紹一下脂肪平台。我們將討論 SOD1，我們將討論我們將用 SOD1 解決的 ALS 部分。

I'm sure I'm forgetting some things. It will be a bit of a busy day. We have a lot going on as you know, Maury, and we hope to touch on most of what we're doing.

我確定我忘記了一些事情。這將是忙碌的一天。正如你所知，我們有很多事情要做，Maury，我們希望能談談我們正在做的大部分事情。

And anything additional you could say about the PALISADE study, sounds like that's moving along and you'll have that readout second quarter of next year. Will you provide more on the types of patients that you've enrolled into this study, is that something we can learn more about this year?

關於 PALISADE 研究，你可以說的任何其他內容，聽起來都在進行中，你將在明年第二季度獲得該讀數。你能提供更多關於你參加這項研究的患者類型的信息嗎？這是我們今年可以了解的更多信息嗎？

Sure. I think we will review the entry criteria, and that would give you a really good idea, but I don't think we're going to look at the baseline (inaudible) and report that ahead of the end of the studies. This is a Phase 3 registration study. It is going really well. So, I will review the key inclusion criteria so you get a sense of the patient population.

當然。我認為我們會審查進入標準，這會給你一個非常好的主意，但我認為我們不會查看基線（聽不清）並在研究結束前報告。這是一項 3 期註冊研究。它真的很順利。因此，我將回顧關鍵的納入標準，以便您了解患者群體。

For our next caller, we have Eliana Mural with UBS. Please go ahead. Your line is now open.

對於我們的下一個來電者，我們有來自瑞銀的 Eliana Mural。請繼續。您的線路現已開通。

Hey guys. Thanks so much for taking the question and congrats on the recent pulmonary data. Maybe just in terms of the patient cohorts that we can expect later this year. I guess, how should we think about what endpoints in particular you'll be reporting out, I guess, between, like, Feno FeV1, and what you'll be looking to see in some of that early data? Thanks.

大家好。非常感謝您提出問題並祝賀最近的肺部數據。也許就我們今年晚些時候可以預期的患者群體而言。我想，我們應該如何考慮您將特別報告哪些端點，我想，在 Feno FeV1 之間，以及您希望在一些早期數據中看到什麼？謝謝。

James, do you want to address that?

詹姆斯，你想解決這個問題嗎？

Sure. Yeah. So for RAGE, we're enrolling patients with mild-to-moderate asthma and I think these are relatively small cohorts. So, they're not powered for FeV1, although we will be measuring FeV1. Some of the key biomarkers that I think could be indicative of pathway engagement that knocking down a RAGE is affecting the inflammatory pathways are things like Feno, which is an IL-13 driven parameter, where we're also measuring blood and sputum eosinophils. I think that will be interesting as well. And Periostin is also IL-13 driven. And then as you mentioned, FeV1 and spirometry.

當然。是的。因此，對於 RAGE，我們正在招募輕度至中度哮喘患者，我認為這些患者相對較小。因此，儘管我們將測量 FeV1，但它們並未為 FeV1 提供動力。我認為一些關鍵生物標誌物可能表明抑制 RAGE 正在影響炎症通路的通路參與是像 Feno 這樣的東西，它是一個 IL-13 驅動參數，我們也在測量血液和痰嗜酸性粒細胞。我認為這也會很有趣。 Periostin 也是由 IL-13 驅動的。然後正如您提到的，FeV1 和肺活量測定法。

Just a quick follow-up. I mean, maybe just what your latest thinking around what the clinically meaningful level of target not found, I'd be left to sort of select to go forward doses and how this could differ between RAGE and MUC5AC?

只是快速跟進。我的意思是，也許您最近對未發現具有臨床意義的目標水平的想法是什麼，我將不得不選擇繼續服用劑量，以及這在 RAGE 和 MUC5AC 之間有何不同？

Yeah. So that's a really good question, that's one that we just can't answer. No one has been able to reduce expression of MUC5AC or RAGE in the past or MMP7 for that matter. And so there's just – we don't have a good biomarker for what that [bogey] could be. We will say however though for RAGE, for instance, we were seeing Mean max knocked down after 2 doses. In the serum at least at around 80%. In the animal models that we have studied, that was more than enough to affect phenotype.

是的。所以這是一個非常好的問題，這是一個我們無法回答的問題。過去沒有人能夠降低 MUC5AC 或 RAGE 的表達，也沒有人能夠降低 MMP7 的表達。所以只是 - 我們沒有一個好的生物標誌物來說明那個 [bogey] 可能是什麼。然而，我們會說，例如，對於 RAGE，我們看到 Mean max 在 2 劑後被擊倒。在血清中至少在80%左右。在我們研究的動物模型中，這足以影響表型。

These are severe models. And so that gives us some confidence. But again, they're just models. And so, we really have to wait to see in humans on what this looks like. We are excited about that level of knockdown. It's a good deep knockdown and it appears to be durable. And so, we are optimistic that that will be – that we are on the board for RAGE and for MUC and for MMP7, as well as for future targets.

這些是嚴格的模型。這給了我們一些信心。但同樣，它們只是模型。因此，我們真的必須等待，看看在人類身上會是什麼樣子。我們對這種程度的擊倒感到興奮。這是一個很好的深度擊倒，而且看起來很耐用。因此，我們樂觀地認為，我們將成為 RAGE、MUC 和 MMP7 以及未來目標的董事會成員。

We believe that because this is a target rich environment, it is – it feels likely to us that if you can knock a gene product down by 80% or so that you're going to affect disease states in at least some of these targets.

我們相信，因為這是一個目標豐富的環境，它是——我們覺得如果你能將一種基因產物減少 80% 左右，你將至少影響其中一些疾病狀態目標。

Our next question comes from the line of Joel Beatty with Baird. One moment.

我們的下一個問題來自 Joel Beatty 與 Baird 的對話。一瞬間。

First one is, how could the profile of ARO-SOD1 potentially compare with Tofersen? And then second question is, can you provide a little more color on why I think eliminating the study of some of the PNH patients from the ARO-C3 study?

第一個是，ARO-SOD1 的配置文件如何與 Tofersen 進行比較？然後第二個問題是，你能否提供更多顏色說明為什麼我認為從 ARO-C3 研究中刪除一些 PNH 患者的研究？

So with regards to SOD1, I think that we will be competitive and likely better in terms of depth of gene target knockdown. And extremely, importantly for this route of administration for intrathecal part of the administration duration, which is key if we can do intrathecal administration every 3 or even every 6 months, I think that it would be much preferable for patients compared to every 2 weeks or every month dosing with Tofersen.

因此，關於 SOD1，我認為我們將具有競爭力，並且在基因目標敲低的深度方面可能會更好。極其重要的是，對於這種鞘內給藥持續時間的給藥途徑，如果我們能夠每 3 個月甚至每 6 個月進行一次鞘內給藥，這是關鍵，我認為與每 2 週或每個月服用 Tofersen。

And then with regards to PNH, it was really a matter of competition that PNH is a small market that's reasonably well addressed with a lot of ongoing competing clinical trials and competing marketed – pursuing to be marketed therapeutics. So, we thought that we have limited resources and best to put those resources to work elsewhere.

然後關於 PNH，這確實是一個競爭問題，PNH 是一個小市場，通過許多正在進行的競爭性臨床試驗和競爭性市場 - 尋求上市治療，可以很好地解決這個問題。因此，我們認為我們的資源有限，最好將這些資源用於其他地方。

Our next question comes from the line of Mani Foroohar.

我們的下一個問題來自 Mani Foroohar。

I'm sorry, did I say your name properly?

對不起，我沒說錯你的名字嗎？

Close enough. Thanks for taking my question.

足夠接近。感謝您提出我的問題。

With SVB, go ahead. Sorry.

使用 SVB，繼續。對不起。

So, I want to dive in a little bit on some of the modeling impact financially, the updates you've given us. Obviously, you've got your NASH program back in your hand out of the HPVs remains in the J&J's hands. You've talked about moving a number of other assets forward, CNS. How should we think about what this means for the tempo of CapEx and OpEx going forward from here? And to what extent is that already contemplated in the commentary you gave us last quarter and prior around ramping CapEx and OpEx spend to drive growth?

所以，我想深入探討一些建模對財務的影響，以及您給我們的更新。顯然，你已經把你的 NASH 程序拿回了你的手中，而 HPVs 仍然在 J & J 的手中。 CNS，你談到了將許多其他資產向前推進。我們應該如何考慮這對未來資本支出和運營支出的節奏意味著什麼？您在上個季度和之前關於增加資本支出和運營支出以推動增長的評論中已經考慮到什麼程度？

Sure. I don't – this was already factored into our plans over the next few years. I don't think anything that's happened over the last couple of quarters has materially changed change those things. We are growing so fast now, Mani, as you know. And we've got 12 clinical programs, 7 of them are wholly-owned. I think we'll have 14 to 16 clinical programs by the end of this year. We have an awful lot of opportunity to partner judiciously. That's – as you know, that's an important part of our model.

當然。我不知道——這已經被納入我們未來幾年的計劃中。我認為過去幾個季度發生的任何事情都沒有實質性地改變這些事情。正如你所知，我們現在發展得如此之快，Mani。我們有 12 個臨床項目，其中 7 個是全資擁有的。我認為到今年年底我們將有 14 到 16 個臨床項目。我們有很多機會明智地合作。那是——如您所知，這是我們模型的重要組成部分。

I believe that we are going to have 20 clinical programs or marketed products by 2025 and no company, I don't think certainly not a company our size can commercialize all of those. And so we have an awful lot of ammunition to find good partners. To bring in non-dilutive capital and that continues to be an important part of our ongoing financial planning. I think that that job gets even easier as we expand these platforms to include CNS to include skeletal muscle, pulmonary adipose.

我相信到 2025 年我們將擁有 20 個臨床項目或上市產品，但沒有一家公司，我認為肯定沒有一家像我們這樣規模的公司可以將所有這些產品商業化。因此，我們有大量的彈藥來尋找好的合作夥伴。引入非稀釋性資本，這仍然是我們正在進行的財務規劃的重要組成部分。我認為隨著我們將這些平台擴展到包括 CNS 以包括骨骼肌、肺脂肪，這項工作會變得更加容易。

We've got an awful lot of opportunity to find good partners, but while still holding on to a very large number of, we think potentially important medicines to drive value for us.

我們有很多機會找到好的合作夥伴，但在保持大量合作夥伴的同時，我們認為潛在的重要藥物可以為我們帶來價值。

Our next question comes from Mayank Mamtani with B. Riley Securities. Your line is now open.

我們的下一個問題來自 B. Riley Securities 的 Mayank Mamtani。您的線路現已開通。

Just maybe on MUC5 and ARO-RAGE, just can you clarify how long or is the chronic tox data available from that – from the preclinical study standpoint? And then at a high level, like the differences between the candidate design delivery, I know the PD market is clear for – clearer for RAGE, but is there anything that we can glean from the different programs that help us think about the de-risking that is underway for the pulmonary delivery? And then I have a quick follow-up.

也許只是在 MUC5 和 ARO-RAGE 上，你能澄清從臨床前研究的角度來看，慢性毒性數據有多長時間或可用嗎？然後在更高的層次上，比如候選設計交付之間的差異，我知道 PD 市場是明確的——對 RAGE 來說更明確，但是我們可以從不同的項目中收集到什麼來幫助我們思考 de -正在進行肺部分娩的風險？然後我有一個快速跟進。

Sure. The chronic tox is not complete – those are ongoing. And then the next question is what is de-risking events? Well, James, do you want to address?

當然。慢性毒素還沒有完全消除——這些還在進行中。然後下一個問題是什麼是去風險事件？好吧，詹姆斯，你想談談嗎？

Want to address more data through this year. We'll have – we will look at – we will have more data on knockdown healthy volunteers shortly. We'll have patient data late this year, and then we'll have the chronic tax data. I guess all of those are somewhat – are incrementally de-risking. We feel really good about the changes we've made in ARO-RAGE, ARO-MUC5AC, ARO-MMP7, compared to ARO-ENAC a year ago. These are substantially more potent constructs.

想通過今年解決更多的數據。我們將擁有——我們將研究——我們將很快獲得更多關於擊倒健康志願者的數據。我們將在今年晚些時候獲得患者數據，然後我們將獲得長期稅收數據。我想所有這些都在某種程度上——正在逐步降低風險。與一年前的 ARO-ENAC 相比，我們對 ARO-RAGE、ARO-MUC5AC、ARO-MMP7 所做的更改感到非常滿意。這些是實質上更有效的構造。

We're using in broad terms, and James correct me if I'm wrong here. Around 1 mg per kg is at this fourth dose that we reported on. A little less than 1 mg per kg. And as you may recall, Mayank, in the pulmonary day a year plus ago, around a year ago, I guess, we graphed the various top studies and where we started to see local lung inflammation and over 6 months. And the cumulative the cumulative doses around 100 mgs per kg where we started to see that inflammation. And so, we feel like we are in good shape here that we should be substantially underneath that for RAGE.

我們使用的是廣義術語，如果我在這裡錯了，James 會糾正我。我們報告的第四次劑量約為每公斤 1 毫克。每公斤略低於 1 毫克。你可能還記得，Mayank，在一年多前的肺病日，我想大約一年前，我們繪製了各種頂級研究的圖表，以及我們開始看到局部肺部炎症和超過 6 個月的地方。累積劑量約為每公斤 100 毫克，我們開始看到炎症。因此，我們覺得我們在這里處於良好狀態，我們應該大大低於 RAGE。

We'll see where we are with MMP7 and with MUC, but at least so far the data we've seen it's encouraging to us that we have something that's extraordinarily more potent than ARO-ENAC. And again remember, I mean again, I know you will recall this. Our dosing for ARO-ENAC was with three daily doses every two weeks.

我們將看到我們在 MMP7 和 MUC 方面的進展，但至少到目前為止，我們看到的數據對我們來說是令人鼓舞的，因為我們擁有比 ARO-ENAC 更強大的東西。再次記住，我的意思是，我知道你會記得這個。我們對 ARO-ENAC 的給藥是每兩週服用三劑每日劑量。

For ARO-RAGE we are once a month and as James pointed out, we have data out through 6 weeks and we are still seeing a deep knockdown. And so this may not be once a month dosing, maybe once every 2 months dosing and then maybe once every 3 months dosing. So, we feel like we're in good shape here.

對於 ARO-RAGE，我們每月一次，正如 James 指出的那樣，我們有 6 週的數據，但我們仍然看到深度擊倒。因此，這可能不是每月給藥一次，可能每 2 個月給藥一次，然後可能每 3 個月給藥一次。所以，我們覺得我們在這裡的狀態很好。

Look forward to seeing more of the R&D day. And then just another high level question. As you've decided on DUX4 muscle, for externalization and not maybe on SOD1 and CNS. So, I mean how are you thinking about which muscle types to go forward with internally versus externally? And for DUX4 muscle, skeletal muscle, are they like kind of deal analogs that exist out there for the kind of value you might be looking for? Thanks for taking our questions.

期待看到更多的研發日。然後是另一個高級問題。正如你已經決定使用 DUX4 肌肉，用於外化而不是 SOD1 和 CNS。所以，我的意思是你如何考慮在內部和外部發展哪些肌肉類型？對於 DUX4 肌肉、骨骼肌，它們是否像現有的交易模擬物一樣具有您可能正在尋找的價值？感謝您回答我們的問題。

Sure. So, let me be clear. We've not made a decision on partnering in ARO-DUX4. We were gearing up to file CTA. We are ready to go. If we even had chronic tox (inaudible), as I mentioned, and we had substantial interest from several companies and we decided to press pause and see where those go. And so that's where we are right now. We'll see if those – if any of those turn into an actual deal, if they do, that's great.

當然。所以，讓我說清楚。我們尚未決定在 ARO-DUX4 中進行合作。我們正準備提交 CTA。我們準備好了。如果我們甚至有慢性毒素（聽不清），正如我提到的那樣，我們對幾家公司產生了濃厚的興趣，我們決定按下暫停鍵，看看它們的去向。這就是我們現在所處的位置。我們會看看這些是否 - 如果其中任何一個變成了實際交易，如果他們這樣做了，那就太好了。

We know hopefully we'll find the right partner for that. If not, that's great too because we believe in the drug, we believe in the platform, and we'd be happy to push that into the clinic ourselves. It just made sense for us to wait a couple of months to see where these things go. We are in a good spot I think for not only ARO-DUX4, but also the follow-on clinical candidate. But as I mentioned, we think we'll be CTA ready in the fourth quarter.

我們知道希望我們能找到合適的合作夥伴。如果沒有，那也很好，因為我們相信這種藥物，我們相信這個平台，我們很樂意自己將其推向臨床。對我們來說，等待幾個月看看這些東西的去向是有意義的。我認為我們不僅對 ARO-DUX4，而且對後續臨床候選藥物都處在有利位置。但正如我提到的，我們認為我們將在第四季度準備好 CTA。

We're in a good spot where we are almost agnostic. I'm happy to bring both those to clinic ourselves, but also I'm happy to listen to offers and if there are good companies who can – who have experience in these types of – in developing these types of drugs and come up with proper value than we have we're happy to talk about that as well.

我們處在一個幾乎不可知論的好位置。我很高興自己將這兩種藥物帶到診所，但我也很高興聽到報價，如果有優秀的公司可以——在這些類型方面有經驗的——開發這些類型的藥物和想出比我們現有的更合適的價值，我們也很樂意談論這一點。

(Operator Instructions) Our next question comes from Patrick Trucchio with HC Wainwright & Company. Patrick, your line is now open.

（操作員說明）我們的下一個問題來自 HC Wainwright & Company 的 Patrick Trucchio。帕特里克，您的線路現已開通。

Just a follow-up question on the CNS platform. I'm wondering if you can discuss the preclinical data that's been generated to date and the level of confidence in the safety profile of these sRNA constructs and delivery methods as you transition to human trials? And then secondly, I'm wondering if there's an update on the HBV program and what that collaboration may look like going forward?

只是 CNS 平台上的後續問題。我想知道您是否可以討論迄今為止生成的臨床前數據，以及在您過渡到人體試驗時對這些 sRNA 構建體和遞送方法的安全性的信心水平？其次，我想知道 HBV 項目是否有更新，以及未來的合作會是什麼樣子？

I'm sure – so let me – I'll give you the high level answer to the CNS question and then and James can give you more granular answer if necessary. So, we have done the [GLP] tox studies and we feel comfortable about safety margins there. We've done exhaustive non-GLP tox studies with ARO-SOD1, as well as other potential candidates and we feel good about what we're seeing.

我敢肯定——所以讓我來——我會給你 CNS 問題的高級答案，然後 James 可以在必要時給你更詳細的答案。因此，我們已經完成了 [GLP] 毒性研究，我們對那裡的安全裕度感到滿意。我們已經對 ARO-SOD1 以及其他潛在候選藥物進行了詳盡的非 GLP 毒性研究，我們對所看到的結果感到滿意。

With respect to HBV, I don't have anything to update you on now. I believe that Janssen is running their process and so I don't have any information on where that's going to be over the next several quarters.

關於乙肝病毒，我現在沒有什麼可以告訴你的。我相信 Janssen 正在運行他們的流程，所以我沒有關於未來幾個季度將在哪裡進行的任何信息。

Yes. I think I would just add on the CNS platform, we'll share more of the specific data at the Analyst Day in June. But we're seeing 80% to 90% reduction in various brain regions in both rodents and non-human primates with good duration that should support at least Q3 month dose administration and we'll share more really next month.

是的。我想我只想在 CNS 平台上添加，我們將在 6 月的分析師日分享更多具體數據。但是我們看到囓齒動物和非人類靈長類動物的各個大腦區域減少了 80% 到 90%，持續時間長，至少應該支持第三季度的劑量管理，我們將在下個月分享更多。

Our next question comes from the line of Keay Nakae with Chardan.

我們的下一個問題來自 Keay Nakae 與 Chardan 的對話。

Question on top. Anything you have learned from Biogen's development to first and that you think you might be able to learn from and benefit from as you proceed into the clinics? Yes. I mean, it's very helpful to have another asset out there that's hitting the same gene target that's kind of gone through the whole process. And I think learned a lot from what they did in their early clinical studies their Phase 1/2 design and then they're pivotal as well?

問題在上。您從百健（Biogen）的發展中學到了什麼，以及您認為在進入臨床階段時可以從中學習並從中受益的是什麼？是的。我的意思是，擁有另一種資產可以擊中在整個過程中經歷的相同基因目標，這非常有幫助。我認為他們從他們在早期臨床研究中所做的 1/2 期設計中學到了很多東西，然後他們也很關鍵？

Yes. And I'd like to add that the regulatory person is very, very important. And the accelerated approval based on the validated biomarker for a disease like this, I think it's huge for the field. It's really important for our program. Will enable us to go a lot faster. I think in this condition and thanks to their work, there is a very good data over the natural history of this SOD1 ALS patient looks like and also was a benchmark for efficacy both in neurofilament and also clinically. So, I think this success program opened the door for advanced – our program even faster.

是的。我想補充一點，監管人員非常非常重要。並且基於針對此類疾病的經過驗證的生物標誌物的加速批准，我認為這對該領域來說意義重大。這對我們的計劃非常重要。將使我們走得更快。我認為在這種情況下，由於他們的工作，有關於這名 SOD1 ALS 患者自然史的非常好的數據，並且也是神經絲和臨床療效的基準。所以，我認為這個成功的項目打開了通往高級的大門——我們的項目更快。

And our next question comes from Prakhar Agrawal with Cantor Fitzgerald. One moment. Your line is opening up now. One moment.

我們的下一個問題來自 Prakhar Agrawal 和 Cantor Fitzgerald。一瞬間。您的線路現在開通了。一瞬間。

The first question is on asthma for targets such as RAGE, given you're testing it in a broad population, how much benefit on lung function endpoint such as FeV1, you think you need to show to give you confidence on moving it into later phase trials trying to better understand what benchmarks are you looking at? And I had a quick follow-up.

第一個問題是針對 RAGE 等目標的哮喘，考慮到您正在廣泛人群中進行測試，它對肺功能終點（例如 FeV1）的益處有多大，您認為您需要證明這一點才能讓您有信心將其轉移到後期階段試圖更好地了解您正在查看哪些基準的試驗？我有一個快速的跟進。

Yes. So, James already made the point that we're not looking at efficacy data in this Phase 1 study. So, this program will require a proper Phase 2 study to show efficacy and probably FeV1. If you look at the benchmark with the biologics that are already approved with the (inaudible), we are looking about 100 milliliters improvement, approximate FeV1. So that's the benchmark, I think, for a Phase 2 study. And that's also something that we will discuss at the Analyst Day in June 1st.

是的。因此，James 已經指出我們在第一階段研究中沒有查看療效數據。因此，該計劃將需要進行適當的 2 期研究來顯示療效，可能還有 FeV1。如果您查看已經通過（聽不清）批准的生物製劑的基準，我們正在尋找大約 100 毫升的改進，近似於 FeV1。所以我認為這是第二階段研究的基準。這也是我們將在 6 月 1 日的分析師日討論的內容。

And just curious as to the broader long-term strategy in asthma, given you have two targets, is the plan to continue developing both assets into Phase 2, Phase 3 or you could make a decision to prioritize one over the other at a certain time and what drives that decision? Thank you.

鑑於您有兩個目標，對於更廣泛的哮喘長期戰略感到好奇，是計劃繼續將這兩項資產開發到第 2 階段、第 3 階段，或者您可以決定在特定時間優先考慮一個而不是另一個是什麼推動了這個決定？謝謝。

Data. It's – as with ANG3 and APOC3, look, these are two targets that are interesting. And they will – and they'll be addressing asthma in two different ways. And so we look forward to seeing how they – how patients respond to each of them. It could be that there are populations of patients who respond better to one than the other, it could be that one is superior in all patient populations. We're just going to have to wait and see.

數據。這是——與 ANG3 和 APOC3 一樣，看，這是兩個有趣的目標。他們會——他們將以兩種不同的方式解決哮喘問題。因此，我們期待看到他們如何——患者如何對他們中的每一個做出反應。可能有一些患者群體對一種藥物的反應優於另一種藥物，也可能是一種藥物在所有患者群體中都更勝一籌。我們只需要拭目以待。

It's a good problem to have because we think we have a good opportunity for both of them to be important medicines. And so, let's just see what the data of the data show over the next couple of years.

這是一個很好的問題，因為我們認為我們有很好的機會讓它們成為重要的藥物。因此，讓我們看看未來幾年數據顯示的內容。

Yes. And the other thing I would say is, MUC5AC is a very new constructive type of drug and there are other new construction diseases that are very prevalent and their memory can be very significant. So, please say we will evaluate total indications such as COPD or bronchiectasis, as well as we go along.

是的。我要說的另一件事是，MUC5AC 是一種非常新的建設性藥物，還有其他非常普遍的新結構疾病，它們的記憶力可能非常重要。所以，請說我們將評估 COPD 或支氣管擴張等總適應症，以及我們的進展。

Our next question comes from Luca Issi with RBC Capital. One moment for your line.

我們的下一個問題來自 RBC Capital 的 Luca Issi。等一下你的台詞。

I have a few, maybe Chris now that you have proof of concept here, I would say for targeting agent, I should say, in lung, how are you thinking about business development? Is this a good time to find a partner? Are you hoping to further the risk of platform before you entertain BD discussions? Or are you planning to keep pulmonary in-house full stop? Any thoughts there would be much appreciated. And maybe on SOD1 ALS, can you just talk about why going after this indication? Obviously, you're a few years behind Biogen, there are only 200 to 300 patients in the United States. So, why not going after other targets with bigger TAMs like maybe (inaudible). So again, any thoughts there appreciated it. And then last one quickly on CapEx, if I recall it correctly, last time you mentioned that you were expecting to invest up to $200 million in CapEx to build the facility in Verona, Wisconsin, however, I think the 10-Q suggests that the number is now between 200 and 260, so wondering if you can clarify that? Thanks so much.

我有幾個，也許克里斯，既然你在這裡有了概念證明，我會說針對代理，我應該說，在肺部，你如何考慮業務發展？現在是尋找合作夥伴的好時機嗎？在進行 BD 討論之前，您是否希望進一步承擔平颱風險？或者你打算保持肺部內部句號？如果有任何想法，我們將不勝感激。也許在 SOD1 ALS 上，你能談談為什麼要追求這個適應症嗎？顯然，你比 Biogen 晚了幾年，美國祇有 200 到 300 名患者。那麼，為什麼不追求其他具有更大 TAM 的目標，比如也許（聽不清）。所以再一次，那裡的任何想法都很感激。然後是關於資本支出的最後一個問題，如果我沒記錯的話，上次你提到你預計將在資本支出上投資高達 2 億美元以在威斯康星州維羅納建造工廠，但是，我認為 10-Q 表明數字現在在 200 到 260 之間，所以想知道您是否可以澄清一下？非常感謝。

Sure. Thanks, Luca. Ken, you want to address the last first?

當然。謝謝，盧卡。肯，你想先解決最後一個問題嗎？

Sure. The 200 that we mentioned was the amount that we thought we were going to spend this year. The total project was anticipated to be $280 million, $290 million in total. We have spent less than the $200 million this year. We expect to spend probably around $90 million more in the second half and probably about $100 million toward that in fiscal 2024.

當然。我們提到的 200 是我們認為今年要花費的金額。該項目預計總投資2.8億美元，共計2.9億美元。我們今年的支出不到 2 億美元。我們預計下半年可能會多支出約 9000 萬美元，並可能在 2024 財年為此支出約 1 億美元。

Okay. So the other two questions. The first one was around pulmonary partnering. So, look, we aren't rushing to partner the current three assets anytime soon or frankly even the broader platform right now. We want to learn more, we want additional data. I don't think that we should be in a hurry to do that. This is an important space for us. As we've said in the past, we don't see 2 or 3 or 4 drugs here. We see 8 or 9 or 10 drugs coming out of the pulmonary platform.

好的。那麼另外兩個問題。第一個是關於肺部合作。所以，看，我們並不急於在短期內或坦率地與更廣泛的平台合作目前的三項資產。我們想要了解更多，我們想要更多的數據。我認為我們不應該急於這樣做。這對我們來說是一個重要的空間。正如我們過去所說，我們在這裡看不到 2 種或 3 種或 4 種藥物。我們看到 8 或 9 或 10 種藥物從肺部平台出來。

There's 16,000 or so pulmonologist in the U.S. we like the idea of building a commercial infrastructure to address that market with several drugs in our own bag. Having said that, it's probably not going to be 10, 11, 12 drugs. So, there will be partnering within this platform, I think at some point, I don't think it makes sense to spend too much time on it at this point because we're still early days. But this is a good opportunity for us. Again internally to create value and to serve patients ourselves, but also to find additional partners in order to really extract proper value from this part of the TRiM platform.

美國有 16,000 名左右的肺科醫生。我們喜歡建立商業基礎設施的想法，用我們自己的袋子裡的幾種藥物來應對這個市場。話雖如此，它可能不會是 10、11、12 種藥物。所以，這個平台內會有合作，我認為在某個時候，我認為在這一點上花太多時間是沒有意義的，因為我們還處於早期階段。但這對我們來說是一個很好的機會。再次在內部創造價值並為患者服務，同時尋找更多的合作夥伴，以便真正從 TRiM 平台的這一部分中提取適當的價值。

The second question I do with SOD1, why are you going after SOD1 instead of something else? Well, I'll tell you. We are also going after something else. We're an and company. We're not an or company. It just so happened that SOD1 popped first and we think it's a good place for us to be. We think we'll stack up well against to a first and as we talked about, it's nice to learn from somebody and accelerate our pathway because somebody went ahead of us, and then if we have a better drug for those patients, then so much better.

我對 SOD1 提出的第二個問題，你為什麼要追求 SOD1 而不是其他東西？好吧，我會告訴你。我們也在追求別的東西。我們是一家公司。我們不是公司。碰巧 SOD1 首先出現，我們認為這是一個適合我們的地方。我們認為我們會很好地對抗第一個，正如我們所說的那樣，向某人學習並加快我們的道路是很好的，因為有人走在我們前面，然後如果我們為這些患者提供更好的藥物，那麼很多更好的。

And so, we believe in SOD1, we believe in helping those patients who need it. But that's just the first of we think many, like the pulmonary space, CNS is a target rich environment and there's no shortage of important targets that we will be going after.

因此，我們相信 SOD1，我們相信幫助那些需要它的患者。但這只是我們認為的第一個，例如肺部空間，CNS 是一個目標豐富的環境，並且不乏我們將追求的重要目標。

Our last question is coming from the line of Madhu Kumar with Goldman Sachs.

我們的最後一個問題來自 Madhu Kumar 與高盛的合作。

So, one kind of science question and then one big strategy question. So, the science question is, what do you think is the fundamental floor for sRAGE and the serum from extrapulmonary resources? Basically, how far do you think serum sRAGE can potentially get to, if you really were to just wipe it out in the lung ?

所以，一種科學問題，然後是一個大戰略問題。所以，科學問題是，您認為 sRAGE 和來自肺外資源的血清的基礎是什麼？基本上，如果您真的只是在肺部將其清除，您認為血清 sRAGE 可能達到多遠？

And then conversely, what is the floor in the lung, I said in bronchoalveolar lavage for sRAGE as well. And then kind of the big picture strategy question is, kind of related to Luca's question. Effectively, like what would you need to see to really reposition the company to focus on these 8, 9 or 10 lung indications relative to the kind of current menagerie of liver directed drugs?

然後相反，肺底是什麼，我在 sRAGE 的支氣管肺泡灌洗中也說過。然後是一個大局戰略問題，有點與盧卡的問題有關。實際上，就像你需要看到什麼才能真正重新定位公司以專注於這 8、9 或 10 個肺部適應症，而不是目前針對肝臟的藥物種類？

Sure. Yes. So the floor of sRAGE, maybe the second part of question is key here. I think measuring – if you assume that the valve sRAGE is exclusively coming from the lung, I mean the floor would be close to zero that you maybe get a small amount of sRAGE coming from endothelium or some of the other cell types, but really the most of the sRAGE in the [bowel] should be coming from the type 2 alveolar epithelial cells.

當然。是的。所以 sRAGE 的地板，也許問題的第二部分是這裡的關鍵。我認為測量——如果你假設閥門 sRAGE 完全來自肺部，我的意思是底值將接近於零，你可能會得到少量來自內皮細胞或其他一些細胞類型的 sRAGE，但是實際上，[腸道] 中的大部分 sRAGE 應該來自 2 型肺泡上皮細胞。

Now, that doesn't mean that we'd be able to get 99.9% knockdown. I think even with our best triggers in the liver, we're getting 95% plus knockdown, so that's just not the way RNAi tends to work. In the serum, I don't think we know the answer to that really. I think the best indication are the data that we've shared so far that you can achieve 90% reduction in the blood. It's not entirely clear how much sRAGE in the blood is coming from extra pulmonary sources.

現在，這並不意味著我們能夠獲得 99.9% 的擊倒率。我認為即使我們在肝臟中有最好的觸發因素，我們也會得到 95% 以上的擊倒，所以這不是 RNAi 傾向於工作的方式。在血清中，我認為我們真的不知道答案。我認為最好的跡像是我們迄今為止共享的數據，您可以將血液減少 90%。目前尚不完全清楚血液中有多少 sRAGE 來自額外的肺部來源。

Although I think it is clear that most of it is coming from the lung. So that number may vary from person-to-person or either in between healthy volunteers and asthma patients. So, I think we're still trying to sort that out, what's the floor in sRAGE in the blood. It was one of the reasons why we added an additional dose level to this healthy volunteer study.

雖然我覺得很明顯，大部分是從肺來的。所以這個數字可能因人而異，或者在健康志願者和哮喘患者之間有所不同。所以，我認為我們仍在努力解決這個問題，sRAGE 在血液中的底線是什麼。這是我們為這項健康志願者研究增加額外劑量水平的原因之一。

I think we're getting very close because we already seen 90%. If you look at APOC3, AAT, that's what you see, 80%, 85%. So, I think we're getting very close to the floor. Almost complete addition.

我認為我們已經非常接近了，因為我們已經看到了 90%。如果你看 APOC3，AAT，就是你看到的，80%，85%。所以，我認為我們已經非常接近地板了。幾乎完成添加。

And so, and Madhu, I'll address the second question. So, I'm just curious. So, when you talk to a J&J and Pfizer and others, do you refer to their large pipeline as menagerie of drugs? So, look, we're not going to refocus this company to be a pulmonary company. I think there's no reason to do that. We actually like this strategy of having a broad pipeline across therapeutic areas.

因此，Madhu，我將解決第二個問題。所以，我只是好奇。所以，當你與強生和輝瑞等公司交談時，你是否將他們龐大的產品線稱為藥物動物園？所以，看，我們不會將這家公司重新定位為一家肺部公司。我認為沒有理由這樣做。我們實際上喜歡這種在治療領域擁有廣泛管道的策略。

I think we can do it in part, but I think we can do it because we are relying on well validated targets and hopefully we stay disciplined and we continue to do that. And so, ultimately I think that we can create the most value by being a relatively diversified company. Pulmonary is a (inaudible). And so that is a place I think that where we will have several or more of our wholly-owned drugs, but that won't be the only one.

我認為我們可以部分做到這一點，但我認為我們可以做到，因為我們依賴經過充分驗證的目標，希望我們保持紀律並繼續這樣做。因此，最終我認為我們可以通過成為一家相對多元化的公司來創造最大的價值。肺部是（聽不清）。因此，我認為這是一個地方，我們將擁有幾種或更多的全資藥品，但這不會是唯一的。

Alright. Thank you all so much for your questions. I would now like to turn it back to Chris Anzalone for our closing remarks.

好吧。非常感謝大家的提問。現在我想把它轉回給 Chris Anzalone 做我們的結束語。

Thanks very much for joining us today, and we look forward to speaking with you on June 1.

非常感謝今天加入我們，我們期待在 6 月 1 日與您交談。

Goodbye. Alright. Making sure you all can you hear me. Thank you for your participation in today's conference. This does conclude the program. You all may now disconnect if you haven't already.

再見。好吧。確保你們都能聽到我的聲音。感謝您參加今天的會議。這確實結束了程序。如果你還沒有，你們現在都可以斷開連接。