Arrowhead Pharmaceuticals Inc (ARWR) 2025 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，歡迎參加 Arrowhead Pharmaceuticals 電話會議。（操作員指令）

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

現在，我將會議移交給 Arrowhead 投資者關係副總裁 Vince Anzalone。請繼續，文斯。

Good afternoon, and thank you for joining us today to discuss Arrowhead's results for its fiscal 2025 first quarter ended December 31, 2024. With us today from management, our President and CEO, Dr. Chris Anzalone, who will provide an overview of the quarter; Dr. Bruce Given, Interim Chief Medical Scientist, who will provide an update on our cardiometabolic pipeline. Andy Davis, Senior Vice President and Head of Global cardiometabolic franchise, who will provide an update on commercialization activities.

下午好，感謝您今天加入我們，討論 Arrowhead 截至 2024 年 12 月 31 日的 2025 財年第一季度的業績。今天，我們的管理階層、總裁兼執行長 Chris Anzalone 博士將概述本季的情況；臨時首席醫學科學家 Bruce Given 博士將提供有關我們的心臟代謝管道的最新進展。高級副總裁兼全球心臟代謝特許經營負責人安迪戴維斯 (Andy Davis) 將提供商業化活動的最新進展。

Dr. James Hamilton, Chief of Discovery and Translational Medicine, who will discuss our earlier-stage development program and Ken Myszkowski, our Chief Financial Officer, who will give a review of the financials. We will then open up the call to questions. 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 and Exchange Act of 1934.

發現和轉化醫學首席 James Hamilton 博士將討論我們早期的開發計劃，而我們的財務長 Ken Myszkowski 將對財務狀況進行審查。然後我們將開始提問。在我們開始之前，我想提醒您，今天電話會議上發表的評論包含《1933 年證券法》第 27A 條和《1934 年證券交易法》第 21E 條所定義的某些前瞻性陳述。

All statements other than statements of historical facts are forward-looking statements and are subject to numerous risks and uncertainties that could cause actual results to differ materially from those expressed in any forward-looking statements.

除歷史事實陳述之外的所有陳述均為前瞻性陳述，並且受多種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 the Form 10-Q. I'd now like to turn the call over to Chris Anzalone, President and CEO. Chris?

有關這些風險和不確定性的更多詳細信息，請參閱我們的 SEC 文件，包括我們最近的 10-K 表年度報告和 10-Q 表季度報告。現在我想將電話轉給總裁兼執行長 Chris Anzalone。克里斯？

Thanks, Vince. Good afternoon, everyone, and thank you for joining us today. Earlier today, we announced that the license and collaboration agreement with Sarepta Therapeutics is closed. Arrowhead expects to receive a $500 million upfront payment in the next 10 days and has already received $325 million through the purchase by Sarepta of Arrowhead common stock priced at $27.25 per share. Arrowhead will also receive $250 million to be paid in annual installments of $50 million over 5 years and has the potential to receive an additional $300 million in near-term payments associated with the continued enrollment of a Phase I/II study of ARO DM1, which we are on track to achieve during the next 12 months.

謝謝，文斯。大家下午好，感謝大家今天的參與。今天早些時候，我們宣布與 Sarepta Therapeutics 的許可和合作協議已經結束。Arrowhead 預計將在未來 10 天內收到 5 億美元的預付款，並且已透過 Sarepta 以每股 27.25 美元的價格收購 Arrowhead 普通股獲得了 3.25 億美元。Arrowhead 還將獲得 2.5 億美元，分 5 年每年支付 5000 萬美元，並有可能獲得額外的 3 億美元短期付款，與繼續招募 ARO DM1 的 I/II 期研究有關，我們將在未來 12 個月內實現這一目標。

Taken together, this adds up to $1.375 billion in cash payments. We are also eligible to receive development milestone payments of between $110 million and $410 million per program and sales milestone payments between $500 million and $700 million per program. The total potential value of this deal, including upfront payments, equity investments and potential milestone payments exceeds $11 billion. On top of that, we are also eligible to receive tiered royalties on commercial sales. This was clearly a big deal and a critical step for Arrowhead to bring balance back to our business model, which in part relies on partnering noncore assets to provide capital for us to develop and commercialize our own wholly owned assets.

加起來，現金支付總額高達 13.75 億美元。我們還有資格獲得每個項目 1.1 億至 4.1 億美元的開發里程碑付款以及每個項目 5 億至 7 億美元的銷售里程碑付款。這筆交易的總潛在價值（包括預付款、股權投資和潛在的里程碑付款）超過 110 億美元。除此之外，我們還有資格獲得商業銷售的分級版稅。這顯然是一件大事，也是 Arrowhead 恢復業務模式平衡的關鍵一步，該模式在一定程度上依賴於與非核心資產合作，為我們開發和商業化我們自己的全資資產提供資金。

In addition to the substantial immediate capital infusion, the deal also accomplishes a few equally important goals. One brings in a partner with extensive development, regulatory and commercial expertise for development of drugs they have in-licensed. Two, increases Arrowhead's focus in the cardiometabolic space. Three, reduces the forward growth in our R&D expenses as Sarepta assumes clinical development responsibilities for multiple programs. And four, provides the potential for substantial downstream nondilutive capital as milestones and ultimately royalties earned.

除了立即註入大量資本外，該交易還實現了一些同樣重要的目標。一家公司引入具有豐富開發、監管和商業專業知識的合作夥伴來開發其許可的藥物。二、增加 Arrowhead 在心臟代謝領域的關注。三、由於 Sarepta 承擔多個項目的臨床開發責任，減少了我們研發費用的未來成長。第四，為大量下游非稀釋性資本提供了潛力，作為里程碑和最終獲得的特許權使用費。

We are now funded into 2028 and potentially through multiple commercial launches by Arrowhead and our partners. We believe we are now well positioned for growth in 2025 and beyond. We see three primary value drivers fueling this growth from our internal development activities in the near term. These are plozasiran, obesity and CNS. Let's begin with plozasiran.

我們目前已獲得到 2028 年的資金，並可能透過 Arrowhead 和我們的合作夥伴進行多次商業發布。我們相信，我們現在已經為 2025 年及以後的成長做好了準備。我們看到，近期有三個主要價值驅動因素將推動我們的內部開發活動成長。這些是 plozasiran、肥胖症和中樞神經系統。讓我們從 plozasiran 開始。

We expect our first commercial launch of plozasiran to drive substantial growth. Pending positive FDA review and approval, launch could take place late this year. We see the value proposition of plozasiran in FCS is quite clear and a substantial differentiation from any other available therapy. We think the magnitude and consistency of tirglyceride lowering, the potential ability to get patients to tirglyceride goal convenient quarterly dosing schedule and well-tolerated safety profile simply make plozasiran a very difficult drug candidate to compete against. But this is just the first step.

我們預計 plozasiran 的首次商業發布將帶來大幅成長。等待 FDA 的積極審查和批准後，該產品可能會在今年稍後上市。我們認為 plozasiran 在 FCS 中的價值主張非常明確，並且與任何其他可用療法都有實質的區別。我們認為，降低三酸甘油酯的幅度和一致性、使患者達到三酸甘油酯目標的潛在能力、方便的季度給藥計劃和耐受性良好的安全性，使 plozasiran 成為一種很難競爭的候選藥物。但這只是第一步。

We are also confident that our current Phase III studies, SHASTA-3, 4 and 5 have the potential to show similar differentiation and value in the much larger severe hypergglyceridemia or SHTG, population and we believe this represents an attractive and underappreciated commercial opportunity. We are now on pace to complete enrollment for the registration of SHASTA-3, SHASTA-4 and MUIR three studies this year which would enable study completion in 2026 and a subsequent sNDA filing. That would substantially broaden the reach of plozasiran and provide a large opportunity for growth. As we have said in the past, we believe plozasiran has the potential to be a $2 billion to $3 billion per year drug in the SHTG market alone. Turning to obesity.

我們也相信，我們目前的 III 期研究 SHASTA-3、4 和 5 有可能在更大的嚴重高三酸甘油酯血症或 SHTG 族群中顯示出類似的差異化和價值，我們相信這代表著一個有吸引力且被低估的商業機會。我們目前正在按計劃於今年完成 SHASTA-3、SHASTA-4 和 MUIR 三項研究的註冊，這將使我們能夠在 2026 年完成研究並隨後提交 sNDA 申請。這將大大拓寬plozasiran的覆蓋範圍並提供巨大的成長機會。正如我們過去所說的那樣，我們相信 plozasiran 僅在 SHTG 市場上就有可能成為每年價值 20 億至 30 億美元的藥物。轉向肥胖。

We believe our two early-stage programs, ARO-IoN-HPE and ARO-ALK7 represent high-value opportunities with near and midterm data readouts that can provide more clarity on where they may fit in the obesity and metabolic treatment paradigm. James will talk about the status of the programs in a moment, but we see the targets and pathways as very promising.

我們相信，我們的兩個早期項目 ARO-IoN-HPE 和 ARO-ALK7 代表著高價值機會，近期和中期數據讀數可以更清楚地說明它們在肥胖和代謝治療模式中的適用位置。詹姆斯稍後會談論這些項目的現狀，但我們認為這些目標和途徑非常有前景。

Both programs are supported by published human genetic studies and the preclinical data have demonstrated dramatic results with the potential to fill gaps in the current standard of care. The possibility of long-acting agents that spare muscle mass and enabled visceral fat loss without dependence on caloric restriction is exciting indeed. It appears that Arrowhead is the first company to start clinical studies against the INHBE target may currently be the only company able to address the ALK 7 target, which utilizes a new version of our TRiM platform capable of delivering to adipocytes.

這兩個計畫均由已發表的人類遺傳學研究支持，臨床前數據已顯示出顯著的成果，並有可能填補目前治療標準的空白。長效藥物能夠維持肌肉質量，不需要依賴熱量限制就能減少內臟脂肪，這種可能性確實令人興奮。Arrowhead 似乎是第一家針對 INHBE 標靶進行臨床研究的公司，目前也可能是唯一一家能夠解決 ALK 7 標靶的公司，它利用了我們能夠傳遞到脂肪細胞的 TRiM 平台的新版本。

The third area that we see driving near-term growth is our emerging CNS pipeline including the new TRiM platform, which in animal models, appears capable of delivering sRNA across the blood brain barrier, including deep brain distribution using subcutaneous injection. Near-term clinical proof of concept would truly be disruptive, and we think would open the door to treating many millions of patients without adequate options.

我們認為推動近期成長的第三個領域是我們新興的 CNS 管線，包括新的 TRiM 平台，該平台在動物模型中，似乎能夠跨血腦屏障遞送 sRNA，包括使用皮下注射進行深部腦分佈。近期的臨床概念驗證確實會帶來顛覆性的影響，我們認為這將為治療數百萬沒有足夠選擇的患者打開大門。

Our initial efforts with this platform address Huntington's, Alzheimer's and Parkinson's disease, all devastating conditions that lack good treatment options. We believe that HTT, MAPT and alpha-synuclein are the most validated targets in Huntington's, Alzheimer's and Parkinson's, respectively. And these are the targets we are addressing with ARO HTT, ARO MAPT and ARO SNCA respectively.

我們利用該平台進行的初步努力旨在治療亨廷頓氏症、阿茲海默症和帕金森氏症，這些疾病都缺乏良好的治療選擇。我們認為，HTT、MAPT 和 α-突觸核蛋白分別是亨廷頓舞蹈症、阿茲海默症和帕金森氏症中最受認可的標靶。這些是我們分別使用 ARO HTT、ARO MAPT 和 ARO SNCA 解決的目標。

Our preclinical data in nonhuman primates have been very compelling, and we are now focused on completing IND/CTA enabling studies and GMP manufacturing to support early clinical trials. We anticipate having CTAs for ARO HTT and ARO MAPT toward the end of this year and for ARO SNCA in early 2026. Sarepta has the right to take HTT forward, and we are currently focused on keeping MAPT wholly owned. We have not made a decision yet on partnering versus retaining ARO SNCA. As I mentioned, we believe the triumvirate of plozasiran, obesity and CNS will be our primary near-term value drivers.

我們在非人靈長類動物身上獲得的臨床前數據非常令人信服，目前我們專注於完成 IND/CTA 支持研究和 GMP 製造以支持早期臨床試驗。我們預計今年底將推出 ARO HTT 和 ARO MAPT 的 CTA，2026 年初將推出 ARO SNCA 的 CTA。Sarepta 有權推動 HTT 的發展，我們目前專注於維持 MAPT 的全資擁有。我們尚未做出與 ARO SNCA 合作還是保留的決定。正如我所提到的，我們相信 plozasiran、肥胖症和中樞神經系統這三大因素將成為我們近期的主要價值驅動因素。

It is also the way investors should think about our focus. We are building a growing cardiometabolic pipeline, which includes obesity, and we will see where the new CNS platform takes us as clinical data come in. In addition to plozasiran, ARO-ALK7 and ARO-INHBE our cardiometabolic franchise includes zodasiran, our ANGPTL3 targeting drug candidate. We expect to begin a Phase III study in HoFH next quarter with sodasiran. We have a large amount of clinical data with this candidate feel confident that it could be an effective medicine with an attractive dosing schedule in this population.

這也是投資人應該思考我們重點關注的問題。我們正在建立一個不斷發展的心臟代謝管道，其中包括肥胖症，隨著臨床數據的湧入，我們將看到新的 CNS 平台將帶我們走向何方。除了 plozasiran、ARO-ALK7 和 ARO-INHBE 之外，我們的心臟代謝特許經營權還包括 zodasiran，我們的 ANGPTL3 標靶候選藥物。我們預計將於下個季度使用 sodasiran 對 HoFH 開始第三階段研究。我們擁有大量有關該候選藥物的臨床數據，有信心它將成為針對此類人群的有效藥物，並且具有具有吸引力的給藥方案。

This would be a relatively simple addition to our FCS and SHTG sales representatives bags. So the incremental commercial costs associated with this additional potential product are expected to be minimal. The Phase III study will be small, and this is a good use of fairly modest resources for us. Where else can we go in cardiometabolic. As I mentioned, ARO ALK 7 is important not only because of the compelling targeted treat obesity, but also as a proof of concept that we can address the dippicites.

這對我們的 FCS 和 SHTG 銷售代表包來說是一個相對簡單的補充。因此，與此額外潛在產品相關的增量商業成本預計會很小。第三階段的研究規模較小，對我們來說，這是對相當適度的資源的良好利用。在心臟代謝方面我們還能去哪裡？正如我所提到的，ARO ALK 7 之所以重要，不僅是因為它具有令人信服的針對性治療肥胖症的功能，而且還證明了我們可以解決肥胖症。

Adipose is the largest endocrine organ in the body, and as such, is expected to be a rich environment for cardiometabolic and obesity targets. We expect to build this out. Similarly, we believe the initial candidates built on our new CNS platform are important because of the neurological targets they address, representing some of the most challenging poorly treated public health crisis remaining and also because they offer the possibility of disruptive clinical proof of concept.

脂肪是人體內最大的內分泌器官，因此，預計成為心臟代謝和肥胖目標的豐富環境。我們希望實現這個目標。同樣，我們認為在我們新的 CNS 平台上建構的初始候選藥物非常重要，因為它們針對的神經系統目標代表了一些最具挑戰性的、治療效果不佳的公共衛生危機，同時也因為它們提供了顛覆性臨床概念驗證的可能性。

We also see important opportunities to develop additional obesity candidates based on new CNS targets. Remember that RNAi is a rifle shot and as our understanding of obesity increases, we see a role for highly specific intervention that could only be practical with systemic delivery.

我們也看到了根據新的中樞神經系統目標開發更多肥胖候選藥物的重要機會。請記住，RNAi 是步槍射擊，隨著我們對肥胖的了解不斷增加，我們看到了高度特異性幹預的作用，而這種幹預只有透過系統性遞送才能實現。

We believe that this has the possibility to treat difficult diseases with reduced risk of safety and tolerability challenges that have led to so much disappointment in the CNS drug development space. This year, we also plan to expand our cardiometabolic presence with a CTA for our first dimer. It is designed to silence expression of both APOC3 and PCSK9 and we hope it will combine the triglyceride lowering qualities of plozasiran with the LDL-C lowering properties of other PCSK9 inhibitors. With this focus on cardiometabolic and a wait and see with CNS, we have a number of programs that are noncore. These are potential partnering opportunities and could bring additional immediate and long-term capital.

我們相信，這有可能治療疑難雜症，並降低安全性和耐受性風險，而安全性和耐受性風險是導致中樞神經系統藥物開發領域中如此多失望的原因。今年，我們也計劃透過第一個二聚體的 ​​CTA 來擴大我們在心臟代謝領域的影響力。它旨在抑制 APOC3 和 PCSK9 的表達，我們希望它能夠結合 plozasiran 的降低三酸甘油酯的特性與其他 PCSK9 抑制劑的降低 LDL-C 的特性。由於重點關注心臟代謝並對中樞神經系統進行觀望，我們有許多非核心項目。這些都是潛在的合作機會，可以帶來額外的短期和長期資本。

Janssen generated compelling clinical data with ARO PNPLA3 and addressing a genetically defined mash population that could number in the 10 million persons range in the major pharmaceutical markets could be attractive to the right company. This is a program for which we will seek a partner. We have learned much about our pulmonary platform through the various clinical programs. It appears to be well tolerated and quite effective at delivering to the deep lung. It is our intention to find a good partner to help identify new deep lung targets and develop a suite of candidates.

楊森利用 ARO PNPLA3 產生了令人信服的臨床數據，並針對主要製藥市場中可能數量達 1000 萬人的基因定義的糊狀人群，這對合適的公司來說可能具有吸引力。這是一個我們尋求合作夥伴的計畫。我們透過各種臨床計畫對我們的肺部平台有了更多的了解。看起來它的耐受性很好，而且輸送到肺部深處非常有效。我們的目的是尋找一個好的合作夥伴來幫助確定新的深層肺目標並開發一套候選人。

Similarly, we have been very impressed with knockdown data coming out of the ARO-RAGE clinical studies. But given the complexity and expense associated with developing this as an asthma and/or COPD drug, we will seek a partner for Phase II and beyond. Clinical data from both ARO C3 and ARO CFB have been quite good and both candidates appear to do what they are designed to do. There are clear markets one or both could address, including C3 glomerulopathy IgA nephropathy and certain lupus populations. We would like to find the right partners to develop these candidates.

同樣，ARO-RAGE 臨床研究得出的擊倒數據給我們留下了深刻的印象。但考慮到將其開發為氣喘和/或 COPD 藥物的複雜性和費用，我們將尋求第二階段及以後的合作夥伴。ARO C3 和 ARO CFB 的臨床數據都相當不錯，而且兩種候選藥物似乎都能達到其設計的預期效果。其中一種或兩種藥物都可以針對特定的市場，包括 C3 腎小球病、IgA 腎病和某些狼瘡人群。我們希望找到合適的合作夥伴來培養這些候選人。

This is where we are now and what we see as key growth drivers for the future. Let's review how we got here and a few key accomplishments from the quarter and since our last earnings call. First and more importantly, the US, FDA accepted the new drug application for investigational plozasiran for the treatment of familial colon micronemia syndrome. This is our first NDA filing, which is a key milestone for Arrowhead, and we are pleased that it was accepted for filing.

這就是我們現在所處的狀況，也是我們視為未來的關鍵成長動力。讓我們回顧一下我們是如何走到今天這一步的，以及本季和自上次財報電話會議以來取得的一些關鍵成就。首先也是最重要的一點，美國FDA接受了plozasiran用於治療家族性結腸微小血症症候群的新藥試驗申請。這是我們的第一份保密協議 (NDA) 申請，這對 Arrowhead 來說是一個重要的里程碑，我們很高興申請被接受。

The FDA provided a PDUFA action date of November '18 to 2025 and indicated it is not currently planning to hold an advisory committee meeting. We now know the potential launch date pending FDA review and approval, so we continue our work to be ready for an efficient launch on day one. Andy will talk about the work in a moment. Sticking with plozasiran, in November, we announced new results from the Phase III PALISADE study and the open-label extension from our Phase II MUIR and SHASTA-2 studies. These data were presented in two oral presentations at the American Heart Association Scientific Sessions 2024 and PALISADE data were simultaneously published in the AHA Journal circulation.

FDA 給出了 2018 年 11 月至 2025 年的 PDUFA 行動日期，並表示目前不打算召開諮詢委員會會議。我們現在知道了等待 FDA 審查和批准的可能發布日期，因此我們將繼續努力為第一天的高效發布做好準備。安迪稍後將談論這項工作。我們繼續研究 plozasiran，11 月，我們公佈了第三階段 PALISADE 研究的新結果以及第二階段 MUIR 和 SHASTA-2 研究的開放標籤擴展結果。這些數據在 2024 年美國心臟協會科學會議上的兩次口頭報告中進行了介紹，PALISADE 數據同時在 AHA 期刊發行版中發表。

The data continued to be promising across studies across the spectrum of triglyceride disorders and after short- and long-term follow-up. In addition, plozasiran has been overall generally well tolerated to date. During the quarter, we also initiated a Phase I/II clinical trial of our first obesity candidate, ARO INHBE and recently received regulatory clearance in New Zealand to initiate the clinical study of our second obesity candidate, ARO ALK 7.

針對各種三酸甘油酯紊亂疾病的研究以及短期和長期隨訪，數據仍然令人鼓舞。此外，迄今為止，plozasiran 總體耐受性良好。在本季度，我們也啟動了我們的第一個肥胖症候選藥物 ARO INHBE 的 I/II 期臨床試驗，並最近獲得新西蘭監管部門的批准，啟動我們第二個肥胖症候選藥物 ARO ALK 7 的臨床研究。

As I mentioned, these programs represent potential drivers for growth for Arrowhead, so we are excited to get both moving into and through early clinical studies. Lastly, we presented interim healthy volunteer results from a Phase I/II clinical study of ARO CFP for the treatment of complement-mediated diseases. Data have been compelling so far, and we anticipate additional data readouts later this year.

正如我所提到的，這些項目代表了 Arrowhead 成長的潛在動力，因此我們很高興能夠進入並完成早期臨床研究。最後，我們展示了 ARO CFP 治療補體介導疾病的 I/II 期臨床研究的健康志願者中期結果。到目前為止的數據都很引人注目，我們預計今年稍後還會有更多數據公佈。

With that overview, I'd now like to turn the call over to Dr. Bruce Given. Bruce?

在了解上述概述後，我現在想將電話轉給布魯斯·吉文博士。布魯斯？

Thank you, Chris. Good afternoon, everyone. As Chris mentioned, the big highlight for the clinical and regulatory teams was the submission and subsequent acceptance of our first new drug application or NDA by the US FDA for investigational plozasiran for the treatment of familial chylomicronemia syndrome, or FCS. The FDA provided a PDUFA action date of November 18, 2025 and indicated is not currently planning to hold an advisory committee meeting.

謝謝你，克里斯。大家下午好。正如克里斯所提到的，對於臨床和監管團隊來說，最大的亮點是我們向美國 FDA 提交了第一份新藥申請或 NDA，並隨後獲得接受，該申請用於研究 plozasiran，用於治療家族性乳糜微粒血症綜合徵（FCS）。FDA 給出了 2025 年 11 月 18 日的 PDUFA 行動日期，並表示目前沒有計劃召開諮詢委員會會議。

We also expect to submit approval applications to additional global regulatory authorities in coming months, for plozasiran for the treatment of patients with FCS. FCS is a severe and rare disease that often is caused by various monogenic mutations that lead to extremely high triglyceride levels. The normal level is triglycerides below 150 milligrams per deciliter, but patients with FCS typically have triglycerides in the thousands.

我們也預計在未來幾個月向其他全球監管機構提交 plozasiran 用於治療 FCS 患者的核准申請。FCS 是一種嚴重且罕見的疾病，通常由導致極高三酸甘油酯水平的各種單基因突變引起。正常水平是三酸甘油酯每分升低於 150 毫克，但 FCS 患者的三酸甘油酯水平通常高達數千毫克。

Such severe elevations can lead to various serious signs and symptoms including acute and potentially fatal pancreatitis, chronic abdominal pain, which can be as frequently as daily, diabetes and cognitive issues. The clinical basis of the NDA submission is comprised of the findings in the Phase III PALISADE study, which were positive with supportive confirmatory evidence from the from the Phase II clinical studies of the SUMMIT program.

如此嚴重的升高可能導致各種嚴重的徵兆和症狀，包括急性和可能致命的胰臟炎、每日頻繁的慢性腹痛、糖尿病和認知問題。NDA 提交的臨床基礎包括第三階段 PALISADE 研究的結果，這些結果是積極的，並獲得了 SUMMIT 計劃第二階段臨床研究的支持性確認證據。

PALISADE successfully met its primary endpoint in all multiplicity-controlled secondary endpoints, including statistically significant reductions in triglycerides, APOC3 and the incidence of acute pancreatitis. In PALISADE, plozastiran achieved deep and durable reductions in triglycerides with median changes from baseline of approximately 80% in the plozasiran 25-milligram group and a statistically significant 83% reduction in the risk of developing acute pancreatitis compared to placebo in the pooled plozasiran 25-milligram and 50-milligram group.

PALISADE 在所有多重控制次要終點中成功達到了其主要終點，包括三酸甘油酯、APOC3 和急性胰臟炎發生率的統計顯著降低。在 PALISADE 研究中，plozastiran 25 毫克組實現了三酸甘油酯的深度和持久降低，與基線相比，plozasiran 25 毫克組的中位變化量約為 80%，而與合併 plozasiran 25 毫克和 50 毫克組相比，急性胰臟炎的風險顯著降低了 83%。

Overall, plozasiran has been generally well tolerated to date. In the PALISADE study, the most frequently reported treatment emergent adverse events for the 25-milligram dose that is proposed for marketing approval were abdominal pain, COVID-19, nasopharyngitis and nausea. In addition to FCS, we are making good progress on the other Phase III studies in the SUMMIT program.

總體而言，迄今為止，plozasiran 的耐受性良好。在 PALISADE 研究中，提議獲得上市批准的 25 毫克劑量最常見的治療出現的不良事件是腹痛、COVID-19、鼻咽炎和噁心。除了FCS之外，我們在SUMMIT計劃的其他第三階段研究方面也取得了良好的進展。

These are SHASTA-3, SHASTA-4 in patients with severe hypertriglyceridemia, or SHTG, and MUIR 3 in patients with mixed hyperlipidemia. The SHASTA studies are designed to assess safety and efficacy and the MIRROR study is to provide additional safety data needed for the expected SHTG supplement to our plozasterine NDA.

這些是針對嚴重高三酸甘油酯血症或 SHTG 患者的 SHASTA-3、SHASTA-4 以及針對混合性高脂血症患者的 MUIR 3。SHASTA 研究旨在評估安全性和有效性，而 MIRROR 研究旨在為我們的普扎斯特林 NDA 預期 SHTG 補充提供所需的額外安全數據。

The SHASTA studies are global, randomized, double-blind, placebo-controlled Phase III studies to evaluate the efficacy and safety of plozastiran in adult patients with SHTG and prior documented evidence fasting triglyceride levels greater than 500 milligrams per deciliter. Eligible subjects will be randomized to receive either plozasiran at 25 milligrams or placebo. The double-blind treatment period duration will be 1 year where subjects received a total of four quarterly doses.

SHASTA 研究是一項全球性、隨機、雙盲、安慰劑對照的 III 期研究，旨在評估普札斯蒂蘭對 SHTG 成年患者和先前有記錄證據表明空腹三酸甘油酯水平大於 500 毫克/分升的療效和安全性。符合條件的受試者將隨機接受 25 毫克 plozasiran 或安慰劑。雙盲治療期持續 1 年，受試者每季共接受四次劑量治療。

After much, eligible subjects will be offered an opportunity to continue in an optional open-label extension. SHASTA 3 and 4 and MUIR 3 are all enrolling well, and we are on schedule to reach full planned enrollment this year, which would enable study completion in 2026 and subsequent sNDA filing. We are also working towards initiating SHASTA 5, a Phase III study in patients with SHTG that are at high risk of acute pancreatitis.

經過一段時間後，符合條件的受試者將有機會繼續參與可選的開放標籤擴展研究。SHASTA 3 和 4 以及 MUIR 3 的招生情況都很好，我們計劃在今年達到計劃的全部招生人數，這將使我們能夠在 2026 年完成研究並隨後提交 sNDA。我們也正致力於啟動 SHASTA 5，這是一項針對患有急性胰臟炎高風險的 SHTG 患者進行的 III 期研究。

We intend to initiate that study this year. In addition to the Phase III program for plazasiran, we are actively working on a study design and preparation for a Phase III study of zodaseran our investigational RNAi therapeutic candidate designed to reduce production of angiopoietin-like protein 3 or ANGPTL3 which is a liver synthesized inhibitor of lipoprotein lipase and endothelial lipase, in patients with homozygous familial hypercholesterolemia or HoFH.

我們打算今年啟動這項研究。除了 plazasiran 的 III 期研究計劃外，我們還在積極設計和準備 zodaseran 的 III 期研究，zodaseran 是一種在研 RNAi 候選治療藥物，旨在減少純合家族性高膽固醇血症或 HoFH 患者的血管生成素樣蛋白 3 或 ANGPTL3 的產生，ANGPTL3 是一種肝臟合成的脂脂酶和內皮酶脂肪酶。

Following a successful Phase II study called Gateway. We will provide more details on that study when it is initiated later this year. This is another program that makes sense as it is potentially complementary to the medical affairs commercial organizations, we are building to support a plazacerand launch, and there is significant overlap in types of physicians who treat FCS and AFH, both rare and lipid disorders.

繼成功完成名為 Gateway 的第二階段研究後。我們將在今年稍後啟動該研究時提供有關該研究的更多細節。這是另一個有意義的項目，因為它可能對醫療事務商業組織具有補充作用，我們正在建造以支持廣場和發布，並且治療 FCS 和 AFH（包括罕見疾病和脂質疾病）的醫生類型有很大的重疊。

I'll now turn the call over to Andy Davis. Andy?

現在我將電話轉給安迪戴維斯。安迪？

Thank you, Bruce. The recent acceptance of our first NDA by the US FDA for investigation of plozaserin is incredibly energizing for the FCS community. The frequent feedback we received from both physicians and patient societies who have read about plozasiran in last year's publication continues to be very encouraging. They cite several potential differentiating attributes of plozasiran that I will discuss briefly.

謝謝你，布魯斯。美國 FDA 最近接受了我們第一份關於研究普洛扎色林的 NDA，這對 FCS 社群來說是一個極大的鼓舞。我們從閱讀過去年出版物中有關 plozasiran 內容的醫生和患者協會那裡收到了頻繁的回饋，這讓我們感到非常鼓舞。他們列舉了 plozasiran 的幾種潛在的差異化屬性，我將簡要討論一下。

First, the reduction in triglycerides is both deep and durable. As Bruce mentioned in his remarks, in PALISADE, plozasiran reduced triglycerides from baseline by an unprecedented approximately minus 80% as early as month one and maintain this reduction with a minimal variation throughout the full 12-month treatment period.

首先，三酸甘油酯的降低是深度且持久的。正如 Bruce 在評論中提到的那樣，在 PALISADE 中，plozasiran 在第一個月就將三酸甘油酯從基線水平前所未有地降低了約 80%，並且在整個 12 個月的治療期間都保持了這種降低幅度，且變化很小。

Second, people living with FCS for the first time have real hope of achieving triglyceride levels below guideline-directed risk threshold associated with acute pancreatitis, such as 880 and even 500 milligrams per deciliter. At least half of the patients at the 25-milligram dose in PALISADE saw TGs below 500 milligrams per deciliter with approximately 75% achieving levels below 880 milligrams per deciliter.

其次，首次患有 FCS 的人真正有希望將三酸甘油酯水平降至與急性胰臟炎相關的指導性風險閾值以下，例如每分升 880 毫克甚至 500 毫克。在 PALISADE 中，接受 25 毫克劑量治療的患者中至少有一半的三酸甘油酸酯低於每分升 500 毫克，約 75% 的患者三酸甘油酯低於每分升 880 毫克。

To support physician education on guideline-directed risk thresholds, we previously announced the launch of our disease awareness campaign. A key focus of our messaging is to educate the community about expert guidelines which recommend maintaining triglyceride levels below 500 milligrams per deciliter to reduce the risk of acute pancreatitis.

為了支持醫生對指南指導的風險閾值的教育，我們先前宣布啟動疾病宣傳活動。我們訊息傳遞的重點是向社區宣傳專家指南，建議將三酸甘油酯水平維持在每分升 500 毫克以下，以降低急性胰臟炎的風險。

Third, the triglyceride reductions from baseline were consistent in patients with genetically confirmed and clinically diagnosed SCS. Results from PALISADE published in the journal Circulation showed that plozasiran at the 25-milligram dose, induced rapid, deep and sustained reductions from baseline in APOCIII of greater than minus 90% and in triglycerides of approximately minus 80%, independent of gene variants causing FCS.

第三，經基因確診和臨床診斷的 SCS 患者的三酸甘油酯相對於基線的降低是一致的。PALISADE 研究結果發表在《循環》雜誌上，結果顯示 25 毫克劑量的 plozasiran 可使 APOCIII 從基線水平快速、大幅、持續降低超過-90%，甘油三酯降低約-80%，且與引起 FCS 的基因變異無關。

We believe this supports the potential value of plozasiran in patients with clinically diagnosed disease regardless of genetic status. Fourth, plozasiran is the first and only investigational medicine to achieve a statistically significant reduction in the risk of developing acute pancreatitis in patients with genetically confirmed and clinically diagnosed FCS.

我們相信，這支持了 plozasiran 對於臨床診斷為疾病的患者（無論基因狀態如何）的潛在價值。第四，plozasiran是第一個也是唯一一個在統計上顯著降低經基因確診和臨床診斷的FCS患者患有急性胰臟炎風險的在研藥物。

This is truly the outcome of most importance for physicians, patients and payers. And lastly, plozasiran demonstrated generally favorable safety and tolerability with low rates of discontinuation for adverse events and is conveniently dosed every 3 months. potentially reducing the treatment burden on both physicians and patients.

這確實對醫生、患者和付款人來說是最重要的結果。最後，plozasiran 表現出了整體良好的安全性和耐受性，因不良事件而停藥的機率較低，並且每 3 個月服用一次，非常方便。潛在地減輕醫生和患者的治療負擔。

As we prepare for the potential launch of plozasiran at the end of this year, we have built highly experienced market access and marketing organizations and our clinical development colleagues have established a fully operational medical affairs function. Medical science liaisons from medical affairs are in the field conducting scientific exchange, our market access colleagues are presently engaging with payers to communicate clinical and economic evidence, and our National Sales Director will be executing our final field force hiring plans in the coming months. We are on track, and we're incredibly excited about the possibility of bringing investigational plozasterine to FCS patients and their families.

在我們為今年年底推出 plozasiran 做準備時，我們建立了經驗豐富的市場准入和行銷組織，我們的臨床開發同事也建立了全面運作的醫療事務職能。來自醫學事務部的醫學科學聯絡員正在現場進行科學交流，我們的市場准入同事目前正在與付款人溝通臨床和經濟證據，我們的全國銷售總監將在未來幾個月內執行我們最終的現場招聘計劃。我們正按計劃進行，我們對將試驗性的普札斯特林帶給FCS 患者及其家人的可能性感到非常興奮。

I'll now turn the call over to Dr. James Hamilton.

現在我將電話轉給詹姆斯·漢密爾頓博士。

Thank you, Andy. First, I want to give a quick review and update on two of the programs that are part of the Sarepta collaboration, ARO-DUX4 and ARO DM1. These are both muscle targeted programs in Phase I/II studies, which Arrowhead will continue to run until study completion. At which time, Sarepta will assume responsibility for clinical development, and ultimately commercialization. We are currently conducting a Phase I/IIa double-blinded, placebo-controlled dose escalating study to evaluate single and multiple ascending doses of ARO DM1 and up to 48 subjects with myotonic dystrophy.

謝謝你，安迪。首先，我想快速回顧並更新 Sarepta 合作中的兩個專案 ARO-DUX4 和 ARO DM1。這些都是 I/II 期研究中針對肌肉的項目，Arrowhead 將持續運行直至研究完成。屆時，Sarepta 將負責臨床開發並最終實現商業化。我們目前正在進行一項 I/IIa 期雙盲、安慰劑對照劑量遞增研究，以評估 ARO DM1 的單次和多次遞增劑量以及多達 48 名強直性肌肉營養不良症患者。

We're in the dose escalation stage of the study, and we are enrolling patients at a good pace. We expect to reach the enrollment targets in the Sarepta agreement, which would trigger an additional $300 million in payments and potentially have first data to report this year. pending discussions with Sarepta and agreement on disclosure timing. Moving on to the second Sarepta partnered muscle targeted program, ARO-DUX4. This is also in a Phase I/IIa dose-escalating study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of ARO DUX4 in adult patients with FSHD type 1.

我們正處於研究的劑量遞增階段，並且正在以良好的速度招募患者。我們預計將達到 Sarepta 協議中的入學目標，這將引發額外的 3 億美元支付，並可能在今年報告第一批數據。有待與 Sarepta 進行討論並就披露時間達成一致。繼續討論第二個 Sarepta 合作的肌肉目標計劃 ARO-DUX4。這也是一項 I/IIa 期劑量遞增研究，旨在評估 ARO DUX4 對 1 型 FSHD 成年患者的安全性、耐受性、藥物動力學和藥效學。

The study is designed to enroll up to 52 subjects. Like ARO DM1, we are in the dose escalation stage and should have first data available to report this year also pending discussion and agreement with Sarepta. These are both very interesting programs for muscle diseases with no adequate treatments available. Our preclinical data have been very compelling, and we believe the programs have the potential to be best-in-class. Our colleagues at Caressa had extensive neuromuscular development, regulatory and commercial expertise.

研究計劃招募最多 52 名受試者。與 ARO DM1 一樣，我們正處於劑量遞增階段，今年應該會有第一批數據可供報告，同時也有待與 Sarepta 進行討論和達成協議。對於目前尚無足夠治療方法的肌肉疾病來說，這兩項都是非常有趣的項目。我們的臨床前數據非常令人信服，我們相信這些項目有潛力成為一流的。Caressa 的同事擁有豐富的神經肌肉發展、監管和商業專業知識。

So their input at this time is helpful and their strategic direction and involvement in the future clinical development and commercialization will be critical. We have a high degree of confidence that the Sarepta team can help accelerate the programs and maximize the chances for clinical commercial success. I also wanted to give a quick update on our obesity programs, ARO-INHBE and ARO-ALK7.

因此，他們此時的投入是有幫助的，他們對未來臨床開發和商業化的策略方向和參與將至關重要。我們高度相信 Sarepta 團隊能夠幫助加速這些計畫並最大限度地提高臨床商業成功的機會。我還想簡單介紹一下我們的肥胖計畫 ARO-INHBE 和 ARO-ALK7。

These programs are both designed to intervene in a biological pathway regulating fat storage which in an environment of nutrient excess can become dysfunctional and overactive. ARO-INHBE is designed to reduce expression of activity which is a ligand for Adipose ALK 7, while ARO-ALK7 is designed to reduce expression of the ALK 7 receptor itself.

這兩個計畫都是為了介入調節脂肪儲存的生物途徑而設計的，在營養過剩的環境下，脂肪儲存的生物途徑可能會變得功能失調和過度活躍。ARO-INHBE 旨在降低脂肪 ALK 7 配體的活性表達，而 ARO-ALK7 旨在降低 ALK 7 受體本身的表達。

In preclinical models, both programs demonstrated substantial reductions in fat mass versus control while simultaneously preserving lean mass. In addition, both targets are supported by human genetics where loss of function carriers have favorable body composition and metabolic characteristics compared to noncarriers. We always prefer genetically validated targets because we think they reduce biology risk and give important insight into predictive safety and tolerability.

在臨床前模型中，這兩個項目均顯示與對照組相比脂肪量顯著減少，同時維持瘦肉量。此外，這兩個目標都得到人類遺傳學的支持，與非攜帶者相比，功能喪失的攜帶者俱有良好的身體組成和代謝特徵。我們始終青睞經過基因驗證的目標，因為我們認為它們可以降低生物學風險並為預測安全性和耐受性提供重要見解。

For ARO-INHBE, in December, we began dosing in a Phase I/IIa dose-escalating study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of ARO-INHBE in up to 78 adult volunteers with obesity. In part one of the study is designed to assess single and multiple doses of aero inhibit monotherapy in Part 2 of the study is designed to assess ARO-INHBE in combination with tirzepatide, a subcutaneously administered GLP-1 GIP receptor coagonist.

對於 ARO-INHBE，12 月，我們開始進行 I/IIa 期劑量遞增研究，以評估 ARO-INHBE 對多達 78 名成年肥胖志願者的安全性、耐受性、藥物動力學和藥效學。研究的第一部分旨在評估單劑量和多劑量的 ARO 抑制單一療法；研究的第二部分旨在評估 ARO-INHBE 與 tirzepatide（一種皮下注射的 GLP-1 GIP 受體激動劑）的聯合使用。

We see the potential to have initial data from part one of the study later this year. For ARO ALK 7, we recently received regulatory clearance in New Zealand to initiate a Phase I/IIa first-in-human dose escalating study to evaluate the safety, tolerability pharmacokinetics and pharmacodynamics of ARO-ALK7 and up to 90 adult volunteers with obesity. We are completing manufacturing of drug supply as we speak and anticipate dosing to initiate in the middle of the year.

我們有可能在今年稍後獲得該研究第一部分的初步數據。對於 ARO ALK 7，我們最近獲得了新西蘭監管部門的批准，可以啟動 I/IIa 期首次人體劑量遞增研究，以評估 ARO-ALK7 和多達 90 名成年肥胖志願者的安全性、耐受性藥物動力學和藥效學。我們目前正在完成藥品供應的生產，預計將在年中開始給藥。

During the last quarter, we also presented interim clinical data from a Phase I/IIa clinical study of ARO CFP, which targets complement factor B and is being developed as a potential treatment for various complement-mediated diseases. The data were presented at the eighth Complement-based Drug Development Summit.

上個季度，我們也展示了 ARO CFP 的 I/IIa 期臨床研究的中期臨床數據，該研究針對補體因子 B，正在開發為各種補體介導疾病的潛在治療方法。該數據是在第八屆補體藥物開發高峰會上發表的。

Complement Factor B plays an important regulatory role in amplifying complement alternative pathway activation and has been identified as a promising therapeutic target for complement-mediated kidney disease such as IgA nephropathy which is the most common glomerular disease worldwide that carries a high lifetime risk of progression to end-stage renal disease. In the Phase I/II way study, circulating levels of CFB protein were reduced by a mean of up to 90% to date with the duration of response greater than three months.

補體因子B在增強補體旁路活化中起著重要的調節作用，被認為是治療補體介導的腎臟疾病（如IgA腎病）的有希望的治療標靶。在 I/II 期研究中，迄今為止，CFB 蛋白循環水平平均降低了高達 90%，反應持續超過三個月。

Additional data from the higher dose levels in multi-dose cohorts are pending and will be presented at an appropriate medical conference. ARO CFB also demonstrated reductions in measures of alternative complement pathway activation with mean reductions at or approaching 100% in AH50 and Wise lab AP at multiple dose levels. ARO CFB has been generally well tolerated to date with safety data supportive of further clinical development.

多劑量組中更高劑量水平的更多數據尚未公佈，並將在適當的醫學會議上公佈。ARO CFB 也顯示出替代補體途徑活化測量值的降低，在 AH50 和 Wise lab AP 中，多個劑量水準的平均降低達到或接近 100%。到目前為止，ARO CFB 普遍耐受性良好，安全數據支持進一步的臨床開發。

Treatment-emergent adverse events have been mostly mild in severity, with none leading to study drug discontinuation. We look forward to completing Part 1 of the study over the coming months and subsequently look ahead to Part 2 of the study in patients with IgA nephropathy.

治療中出現的不良事件大多嚴重程度較輕，且無一導致停止研究藥物。我們期待在未來幾個月內完成研究的第一部分，並隨後期待針對 IgA 腎病患者的研究的第二部分。

I will now turn the call over to Ken Myszkowski.

現在我將把電話轉給 Ken Myszkowski。

Thank you, James, and good afternoon, everyone. As we reported today, our net loss for the quarter ended December 31, 2024 was $173.1 million or $1.39 per share based on 124.8 million fully diluted weighted average shares outstanding. This compares with a net loss of $132.9 million or $1.24 per share based on $107.4 million fully diluted weighted average shares outstanding for the quarter ended December 31, 2023.

謝謝你，詹姆斯，大家下午好。正如我們今天所報告的那樣，根據 1.248 億股完全稀釋加權平均流通股，我們截至 2024 年 12 月 31 日的季度淨虧損為 1.731 億美元，即每股 1.39 美元。相較之下，根據截至 2023 年 12 月 31 日的季度，淨虧損為 1.329 億美元，即每股 1.24 美元（基於 1.074 億美元的全面攤薄加權平均流通股）。

Revenue for the quarter ended December 31, 2024, was $2.5 million compared to $3.6 million for the quarter ended December 31, 2023. Revenue in the current period relates to our collaboration agreements with GSK, revenue in the prior period, primarily related to the recognition of revenue from our license and collaboration agreements with Takeda and GSK.

截至 2024 年 12 月 31 日的季度營收為 250 萬美元，而截至 2023 年 12 月 31 日的季度營收為 360 萬美元。本期收入與我們與葛蘭素史克的合作協議有關，上期收入主要與我們與武田和葛蘭素史克的許可和合作協議的收入確認有關。

Revenue recognition related to the Sarepta license and collaboration agreement will begin during the quarter ending March 31, 2025. Revenue will be recognized over a period during which we are providing key performance obligations. This is primarily related to our responsibilities to manage certain clinical trials for the clinical candidates to which we granted Sarepta and exclusive license agreement.

與 Sarepta 許可和合作協議相關的收入確認將於截至 2025 年 3 月 31 日的季度開始。收入將在我們提供關鍵履約義務的期間內確認。這主要與我們管理授予 Sarepta 獨家許可協議的臨床候選人的某些臨床試驗的職責有關。

Total operating expenses for the quarter ended December 31, 2024, were $163.9 million compared to $140.1 million for the quarter ended December 31, 2023. The key drivers of this change were increased candidate costs and salaries as the company's pipeline of clinical candidates has both increased and advanced into later stages of development.

截至 2024 年 12 月 31 日季度的總營運費用為 1.639 億美元，而截至 2023 年 12 月 31 日季度的總營運費用為 1.401 億美元。這項變化的關鍵驅動因素是，隨著公司臨床候選藥物的數量不斷增加並進入後期開發階段，候選人成本和薪資也隨之增加。

Net cash used by operating activities during the quarter ended December 31, 2024, was $146.3 million compared to $117.8 million for the quarter ended December 31, 2023. The increase in cash used by operating activities is driven primarily by higher research and development expenses. Turning to our balance sheet. Our cash and investments totaled $552.9 million at December 31, 2024. Including the $825 million in upfront payments from the Sarepta agreements, our pro forma cash and investments would be $1.4 billion at December 31, 2024.

截至 2024 年 12 月 31 日的季度，經營活動所用的淨現金為 1.463 億美元，而截至 2023 年 12 月 31 日的季度為 1.178 億美元。經營活動所用現金的增加主要是因為研發費用的增加。轉向我們的資產負債表。截至 2024 年 12 月 31 日，我們的現金和投資總額為 5.529 億美元。包括 Sarepta 協議中的 8.25 億美元預付款，截至 2024 年 12 月 31 日，我們的預期現金和投資將達到 14 億美元。

Based on our expected cash inflows from the Sarepta agreement Debt repayments as well as other cash burn, we expect our cash and investments balance to be approximately $1 billion at the end of calendar 2025, and we expect to have cash runway into 2028. Our common shares outstanding at December 31, 2024, were $125.6 million.

根據我們預期的 Sarepta 協議債務償還和其他現金消耗所產生的現金流入，我們預計到 2025 年底我們的現金和投資餘額將達到約 10 億美元，並且我們預計到 2028 年將有現金儲備。截至 2024 年 12 月 31 日，我們已發行的普通股為 1.256 億美元。

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

有了這個簡短的概述，我現在將電話轉回給克里斯。

Thanks, Ken. Not only do we see several growth drivers over the coming years. We have a robust potential catalyst calendar in 2025. Throughout the year, we expect multiple events that we believe are important. For plozasiran, we expect the following key events: initiate SHASTA-5 in patients at high risk of acute pancreatitis, fully enroll SHASTA-3, SHASTA-4 and MUIR-3, make additional global regulatory submissions commercial launch in FCS in the US and potentially the EU pending review and approval. Fosedaseran initiate Phase III HoFH study.

謝謝，肯。我們不僅看到未來幾年有多個成長動力。2025年我們有一個強勁的潛在催化劑日曆。我們期待全年舉辦多場我們認為重要的活動。對於 plozasiran，我們預計以下關鍵事件：在急性胰臟炎高風險患者中啟動 SHASTA-5，全面招募 SHASTA-3、SHASTA-4 和 MUIR-3，進行額外的全球監管提交，在美國 FCS 和可能的歐盟進行商業發布，等待審查和批准。Fosedaseran 啟動 III 期 HoFH 研究。

For the obesity programs, we expect to initiate dosing in the Phase I/II study of ARO-ALK7 and potentially have the first data for Part 1 of the Phase I/II study of ARO-ENE. For focisiran, our investigational RNAi candidate partner with Takeda and being developed to treat the liver disease associated with alpha-1 intryption deficiency, we have the potential to reach full enrollment of the Phase III REDWOOD study. For ARO Aero DM1 and ARA MMP-7, we have the potential for initial data in the Phase I/II studies and the potential to achieve $300 million milestone payments from Sarepta.

對於肥胖症項目，我們期望在 ARO-ALK7 的 I/II 期研究中開始給藥，並可能獲得 ARO-ENE 的 I/II 期研究第 1 部分的首批數據。對於 focisiran，我們與武田合作研發的 RNAi 候選藥物，正在開發用於治療與 alpha-1 內切酶缺乏症相關的肝病，我們有可能實現 III 期 REDWOOD 研究的全面招募。對於 ARO Aero DM1 和 ARA MMP-7，我們有可能獲得 I/II 期研究的初步數據，並有可能從 Sarepta 獲得 3 億美元的里程碑付款。

For both complement programs, ARO CFB and ARO C3, we have potential data readouts. And lastly, for the emerging CNS pipeline, we anticipate filing CTAs for our first systemically delivered and subcutaneously administered programs. As always, there's a lot going on at Arrowhead to be excited about. Thank you for joining us today.

對於兩個補體程序 ARO CFB 和 ARO C3，我們都有潛在的數據讀數。最後，對於新興的中樞神經系統 (CNS) 管道，我們預計將為我們的首個系統輸送和皮下給藥項目提交 CTA。像往常一樣，Arrowhead 有很多令人興奮的事情發生。感謝您今天加入我們。

And I would now like to open the call to your questions. Operator?

現在我想開始回答你們的問題。操作員？

(Operator Instructions)

（操作員指令）

Luca SA, RBC Capital.

Luca SA、RBC Capital。

Great, thanks so much for taking my question, and I congrats on closing the deal's wrapped up. Maybe Jane on obesity, I can just talk a little bit more about inhibit. I know you're testing both, but is this fundamentally a play in your head or this is more like an add-on therapy to GLP-1 or whatever is next for this category? And maybe related, can you just talk about what will the downside case for the data later to see here and maybe an upside case for the data later this year, what's the bogey here? So any color there?

太好了，非常感謝您回答我的問題，我祝賀您完成這筆交易。也許簡 (Jane) 談論肥胖，我可以再多談一點關於抑制的事情。我知道您正在對兩者進行測試，但這從根本上來說只是您腦海中的想法，還是更像是 GLP-1 的附加療法，或者是該類別的下一步療法？也許相關的是，您能否談談今年稍後數據可能出現的下行情況以及上行情況，這裡的預期是什麼？那裡有顏色嗎？

Much appreciate it. And then maybe, Bruce, super quickly, we've obviously seen Novartis is pushing out their data to next year for LP. Just wondering what was your reaction to that news? And what does this mean for the broader category, including all pass around. Again, any color there, much appreciated. Thanks so much.

非常感謝。然後也許，布魯斯，很快我們就明顯看到諾華正在將他們的 LP 數據推遲到明年。只是想知道您對這個消息有何反應？這對於包括所有傳播在內的​​更廣泛的類別意味著什麼。再次，無論什麼顏色，都非常感激。非常感謝。

Sure, Thanks, Luca. I can take a shot at the first question. Like you said, we are studying ARO inhibit in monotherapy as well as in combination with tirzepatide. And we'll have to wait and see how the data look.

當然，謝謝，盧卡。我可以嘗試回答第一個問題。正如您所說，我們正在研究 ARO 抑制單一療法以及與 tirzepatide 的聯合療法。我們還需拭目以待，看看數據究竟如何。

We haven't really made a call on what the future path development path look like for that molecule. And similarly, I think we'll just have to wait and see. We don't have really a specific bogey to hit, I think, we'll see how the data evolves on both the monotherapy side and in the combination arms.

我們還沒有真正確定該分子的未來發展路徑是什麼樣的。同樣，我認為我們只需要拭目以待。我認為，我們並沒有真正設定一個特定的目標，我們將觀察單一療法和聯合療法的數據如何發展。

And just to be clear, look, obesity is not a one-size-fits-all condition. And I don't think people who are in it are thinking of it that way. This is a huge number of patients with a variety of different needs. And so we are developing over time, a suite of drug candidates against that could be used in combination with each other in combination with others in combination with existing therapies in combination with new therapies. We are really excited about these two pathways, and we think they're a great step forward.

需要明確的是，肥胖並不是一種針對所有人群的疾病。我不認為身處其中的人會這麼想。這是一個龐大的患者群體，具有各種不同的需求。因此，我們正在隨著時間的推移開發一系列候選藥物，這些藥物可以相互結合使用，與其他藥物結合使用，與現有療法結合使用，與新療法結合使用。我們對這兩條途徑感到非常興奮，我們認為這是向前邁出的一大步。

And it's just not clear how the world is going to use these or, frankly, any other obesity drugs that are coming online.

目前還不清楚世界將會如何使用這些藥物，或者坦白說，任何其他上市的減肥藥物。

Yeah, and finally, your question about Lp(a). I don't have a lot of insight here. We're not on the inside of certainly the Novartis program. We're not on the inside of the Amgen program. So we really don't know.

是的，最後，你的問題是關於 Lp(a)。我對此沒有太多的見解。我們當然不屬於諾華計畫的內部。我們並不參與安進專案。所以我們真的不知道。

I mean, I think in general, I would say that I'm more excited about Olpasiran just because I think it's a more effective agent with respect to knocking down Lp(a). It's certainly more convenient than an antisense approach and probably better tolerated as well. So I'm generally more excited about Olpasiran from a cardiovascular disease perspective. But what's going on with Novartis' compound and frankly, even what's going on with Amgen's compound, I don't have an inside track on that information.

我的意思是，我認為總的來說，我對 Olpasiran 更感興趣，因為我認為它在降低 Lp(a) 方面是一種更有效的藥物。它肯定比反義方法更方便，也可能更容易被接受。因此，從心血管疾病的角度來看，我對 Olpasiran 更感興趣。但諾華的化合物到底發生了什麼，坦白說，甚至安進的化合物到底發生了什麼，我都沒有這方面的內幕消息。

Got it. Thanks so much guys.

知道了。非常感謝大家。

David Lebowitz, Citi.

花旗銀行的 David Lebowitz。

Thank you very much for taking my question. I'm curious in the early days from what you've seen in your doctors regarding APOC3 and current commercial launches. Is there any feedback you're getting from doctors on what they're seeing.

非常感謝您回答我的問題。從您在醫生那裡了解到的有關 APOC3 和當前商業發布的早期情況來看，我很好奇。醫生們對他們所見的情況有什麼回饋嗎？

Yeah, I'm just happy to comment on the feedback that we continue to receive with respect to plozasiran, which, as I mentioned, they view as highly differentiating based on the attributes I spoke to on the call. So I would say, despite the fact that there is an option available, physicians and patient societies continue to remain really enthusiastic about plozasiran.

是的，我很高興對我們繼續收到的有關 plozasiran 的反饋進行評論，正如我提到的，根據我在電話中談到的屬性，他們認為 plozasiran 具有很高的差異化。因此我想說，儘管存在其他選擇，但醫生和患者團體仍然對 plozasiran 充滿熱情。

Thanks for taking my question.

感謝您回答我的問題。

[Elle Murrow], UBS.

[Elle Murrow]，瑞銀。

Hi, This is Jasmine on for Ellie. Congratulations on the announcement today. I just wanted to follow up on it earlier question. So for inhibiting an ELC-7, will we see weight loss data or anything on body competition from the Phase I/IIa trial. And if at this early time point, we won't see that yet.

你好，我是 Jasmine，為 Ellie 主持節目。祝賀今天的公告。我只是想跟進一下之前的問題。因此，對於抑制 ELC-7，我們是否會看到 I/IIa 期試驗中的減肥數據或任何有關身體競爭的數據。如果處於這個早期階段，我們還看不到這一點。

What are you looking for to see from the PK/PD results to give you confidence to move forward. Thanks.

您希望從 PK/PD 結果中看到什麼來給予您繼續前進的信心。謝謝。

Yeah, I think from the Part 1 of the study, the monotherapy arms, we will be looking at body composition based on full body MRI as well as, of course, weight loss. And we'll look at them the usual Phase I metrics, of course, safety and plasma PK, which will likely look like the other GalNAc SiRNAs, and then we can measure the biomarker active in the blood. So that's the direct biomarker of gene target knockdown.

是的，我認為從研究的第一部分，即單一療法組開始，我們將根據全身 MRI 以及減肥來觀察身體組成。我們將研究它們的常見 I 期指標，當然是安全性和血漿 PK，它們可能看起來像其他 GalNAc SiRNA，然後我們可以測量血液中的活性生物標記。這就是基因標靶敲除的直接生物標記。

Great. Thank you.

偉大的。謝謝。

Marie Raycroft, Jefferries.

瑪麗‧雷克羅夫特，傑弗里斯。

Hi, congrats on the progress and thanks for taking my question. I was going to ask about the SHASTA-5 study. I know you plan to start the study in second quarter, and you've mentioned it could include 140 patients and the purpose is mostly for payers. For this study, do you have estimates on what the time line to data could look like? And can you talk more about the strategy here?

你好，恭喜你取得進展，謝謝你回答我的問題。我本來想問一下有關 SHASTA-5 研究的問題。我知道您計劃在第二季度開始這項研究，並且您提到它可能包括 140 名患者，目的主要是為了付款人。對於這項研究，您是否對數據的時間線有估計？能進一步談談這裡的策略嗎？

I guess, could the totality of acute pancreatitis stated derisk and outcomes study or potentially even replace the need to run a CVOT study?

我想，是否可以對急性胰臟炎進行整體風險和結果研究，甚至可能取代進行 CVOT 研究的需要？

So Mary, it's hard to predict. No one's ever attempted a trial like this before that it will be the first ever outcome study focused on pancreatitis as the primary endpoint. It will be enrolling patients that are a clear risk for pancreatitis. So the enrollment time line is sort of to be determined, you might say. And in addition to that, as with the CVOT for instance, it is an outcome study.

所以瑪麗，這很難預測。以前從來沒有人嘗試過這樣的試驗，這將是有史以來第一個以胰臟炎為主要終點的結果研究。它將招募明顯有胰臟炎風險的患者。因此你可能會說，入學時間表還有待確定。除此之外，與 CVOT 一樣，這是一項結果研究。

So we will go until we get the required number of events. So it's not a fixed duration after enrollment is complete. But in fact, it will keep going until the required number of events are seeing. So a couple of levels of uncertainty there. We feel good about it.

我們會一直堅持下去，直到達到所需數量的事件。因此，註冊完成後，持續時間並沒有固定。但事實上，它會一直持續下去，直到看到所需的事件數量。因此，存在幾個層次的不確定性。我們對此感覺很好。

We think it will be well received by clinicians. But in reality, it's hard to really predict exactly when it will happen. We think it will be a very important study though, and we think it will especially be a very important study to payers and to health assessment organizations, especially outside the US, where places like the UK and Germany, these health assessment organizations are very, very important health technology assessment organizations. They're very important.

我們認為它會受到臨床醫生的歡迎。但實際上，很難真正預測它何時會發生。我們認為這將是一項非常重要的研究，我們認為這對付款人和健康評估組織來說尤其是一項非常重要的研究，特別是在美國以外的地方，如英國和德國，這些健康評估組織是非常非常重要的健康技術評估組織。它們非常重要。

They really determine whether or not patients are going to have access to a new drug. So we think this is going to be a revolutionary study, first of its kind practice changing. And it will impact the US as well, but we anticipate less so than it will in Europe. The second part of your question, I didn't quite understand if you were asking whether it would limit the need for CVOT.

他們真正決定了患者是否能夠獲得新藥。因此我們認為這將是一項革命性的研究，首次改變實踐。它也會對美國產生影響，但我們預期其影響會比對歐洲的影響小。關於你問題的第二部分，我不太明白你是在問它是否會限制對 CVOT 的需求。

I don't really think so just because I think that the question of atherosclerotic risk related to triglycerides is really separate from the question of pancreatitis risk. So I think there are two very important risks, but they're really independent questions and especially for patients with milder forms of hypertriglyceridemia where the pancreatitis risk is quite low, but the atherosclerosis risk is still very important.

我並不這麼認為，因為我認為與三酸甘油酯相關的動脈粥狀硬化風險問題與胰臟炎風險問題實際上是無關的。因此，我認為有兩個非常重要的風險，但它們實際上是獨立的問題，特別是對於輕度高三酸甘油酯血症患者，胰臟炎風險相當低，但動脈粥狀硬化風險仍然非常重要。

And we think based on genetic data represents an area of really unmet medical need and persistent residual risk of the cardiovascular disease. We think we're the first drug that's really in a position to truly assess that risk and assess the opportunity for a drug that quite effectively reduces triglycerides to impact that cardiovascular risk.

我們認為，基於基因數據代表著真正未滿足的醫療需求和心血管疾病持續存在的殘留風險。我們認為，我們是第一個能夠真正評估這種風險並評估有效降低三酸甘油酯的藥物影響心血管風險的機會的藥物。

Got it. It's all helpful perspective. Thanks for taking my question.

知道了。這些都是很有幫助的觀點。感謝您回答我的問題。

Edward Tenthoff, Piper Sandler.

愛德華·坦托夫，派珀·桑德勒。

Great, thanks guys. Thanks for all the updates and for everybody as well out there. Question with respect to Europe, overseas of plozasiran. Now that we've gotten the US situation sort of laid out, what are plans for Europe? And would you be partnering overseas?

太好了，謝謝大家。感謝所有的更新以及在場的每個人。關於歐洲、海外的 plozasiran 的問題。現在我們已經了解了美國的情況，那麼對於歐洲有什麼計畫呢？您會與海外合作嗎？

Are there certain thresholds we're waiting for would there have to be additional studies? Just maybe you can update us on sort of what's taking is overseas, both for FCS, but also longer term for severe hypertriglyceridemia.

我們是否正在等待某些閾值，是否需要進行額外的研究？也許您可以向我們介紹海外針對 FCS 以及長期嚴重高三酸甘油脂血症的治療。

Yeah. Thanks for the call. This is Andy. So we're currently -- we're currently planning for commercialization in European markets. along with a commercial partner.

是的。感謝您的來電。這是安迪。所以我們目前——我們目前正在計劃在歐洲市場進行商業化。以及商業夥伴。

And so there'll be more details on that in the future. We're incredibly excited about the large European markets and bringing plozasiran -- investigational plozasiran to those patients there as well.

因此，未來將會有更多關於此的詳細資訊。我們對龐大的歐洲市場感到非常興奮，並希望能夠將 plozasiran——正在研究的 plozasiran 帶給那裡的患者。

Okay. Thank you.

好的。謝謝。

Patrick Trucchio, H.C. Wainwright.

帕特里克·特魯基奧，H.C.溫賴特。

Thanks. Good afternoon, and congrats on the progress here. A couple of follow-ups. The first is just -- can you review how you envision plozasiran's competitive positioning relative to olozarsen in both FCS, so also in the broader severe high triglyceride population. And how these product profiles could compare in the real-world setting, particularly as we look towards the launch upcoming for plozasiran, potential launch cup coming for plozasiran FCS.

謝謝。下午好，祝賀這裡的進展。一些後續行動。首先，您能否回顧一下您如何看待 plozasiran 相對於 olozarsen 在 FCS 以及更廣泛的嚴重高甘油三酯人群中的競爭地位。以及這些產品配置在現實環境中如何進行比較，特別是當我們期待即將推出的 plozasiran 和即將推出的 plozasiran FCS 的發布杯時。

And then just separately, just mentioned the adipose tissue targeting platform. I'm just curious what targets or disease areas do you view as being attractive as you look to build out this programs in this part of the pipeline? And when may you have an update for us on this build-out.

然後只是單獨提到了脂肪組織靶向平台。我只是好奇，當您希望在此部分中建立這些項目時，您認為哪些目標或疾病領域具有吸引力？什麼時候可以向我們報告一下此次擴建的進展？

Thank you for the question. This is Andy. I'll address the first part of your question related to differentiation. I'll speak primarily to the plozasiran data, but I would encourage you to do your own comparison between the balance and PALISADE studies to the extent you want to understand the key differences yourself. I think one of the primary differentiators that we see is around the reduction in triglycerides.

感謝您的提問。這是安迪。我將回答與區分相關的問題的第一部分。我將主要談論 plozasiran 數據，但我鼓勵您自己對平衡和 PALISADE 研究進行比較，以便自己了解主要差異。我認為我們看到的主要區別之一是甘油三酯的減少。

As we've talked about from PALISADE, we see a triglyceride reduction from baseline, which is largely unprecedented, approximately minus 80% from baseline. And we see that as early as month one and then continued throughout that full 12-month treatment period. So I think that's the first point of differentiation 1 would focus on.

正如我們在 PALISADE 中討論的那樣，我們看到三酸甘油酯從基線水平降低，這在很大程度上是前所未有的，大約比基線水平降低了 80%。我們早在第一個月就看到了這一點，並持續整個 12 個月的治療期。所以我認為這是我要關注的第一個區別點。

I think the second point of differentiation is what that means for FCS patients as far as achieving guideline-directed risk thresholds. So many of these society guidelines point to less than 500 milligrams per deciliter as the goal to which they want to get FCS patients below in order to reduce the risk of acute pancreatitis.

我認為第二個區別點是，就達到指南指導的風險閾值而言，這對 FCS 患者意味著什麼。許多社會指南都以低於 500 毫克/分升為目標，他們希望 FCS 患者的血糖水平低於該水平，以降低急性胰臟炎的風險。

So obviously, the larger the TG reduction from baseline, the greater the proportion of FCS patients who are likely to achieve that guideline-directed goal. So we think that's a key area of differentiation as well. And third, in comparison to those studies, you'd have an appreciation for the fact that PALISADE study both genetically confirmed and clinically diagnosed patients.

因此顯然，TG 相對於基線的降低幅度越大，FCS 患者達成指引指導目標的比例就越大。因此我們認為這也是一個關鍵的差異化領域。第三，與這些研究相比，您會欣賞 PALISADE 對基因確診和臨床診斷患者同時進行研究。

And what we saw was that plozasiran was the first and only investigational medicine to achieve a statistically significant reduction in the risk of acute pancreatitis in that population. So again, an important point of differentiation we spoke to acute pancreatitis as an important outcome for payers and patients and physicians.

我們發現，plozasiran 是第一個也是唯一一個在該族群中顯著降低急性胰臟炎風險的試驗藥物。因此，我們再次強調，一個重要的區別是，急性胰臟炎對於付款人、患者和醫生來說都是一個重要的結果。

And so seen a statistically significant difference in PALISADE is an important differentiator. And then lastly, the safety profile has been generally very tolerable with low rates of discontinuation for adverse events. And importantly, we see in every 3-month dosing with plozasiran, and that's different from the alternative. That's only four injections a year and what patients tell us is they prefer fewer injections and what physicians tell us is that helps with compliance and adherence. And so they're quite excited about in every 3-month dosing regimen.

因此可以看出，PALISADE 的統計顯著差異是一個重要的差異因素。最後，安全性總體來說是非常好的，因不良事件而停藥的機率很低。重要的是，我們每 3 個月服用一次 plozasiran 都會看到效果，這與其他替代品不同。每年只需注射四次，患者告訴我們，他們喜歡少注射幾次，醫生告訴我們，這有助於提高依從性和堅持性。因此他們對每 3 個月的給藥方案感到非常興奮。

So that would be I think the final point of differentiation I might point you towards. So those are just a handful of differentiating attributes of plozasiran that we recognize as a team.

所以我認為這就是我要向你指出的最後一個區別點。因此，這些只是我們作為一個團隊認可的 plozasiran 的少數差異化屬性。

So let me chime in too. This is Bruce Given again. I think it's a little easier to kind of put balance in PALISADE side by side than it is to necessarily put SHASTA-2 I and the currently available data for SHTG with olezarsen side by side because the Bridge–TIMI study covered both mixed hyperlipidemia and a small number of patients that reached into SHTG. So it's a little harder to sort of understand what they're going to look like, what olezarsen is– going to look like in SHTG. I think we have a pretty good idea of what we would predict is going to be seen with plozasiran because I think it's very likely that SHASTA gives us a pretty good idea of what we're going to see there.

因此，請允許我也加入討論。我是布魯斯·吉文。我認為將 PALISADE 與 SHASTA-2 I 以及目前可用的 SHTG 與 olezarsen 數據並列起來進行平衡要容易一些，因為 Bridge-TIMI 研究涵蓋了混合性高脂血症和少數涉及 SHTG 的患者。因此，要理解它們會是什麼樣子，以及 olezarsen 在 SHTG 中會是什麼樣子，就有些困難了。我認為我們對 plozasiran 的預測結果有很好的了解，因為我認為 SHASTA 很可能讓我們很好地了解我們將在那裡看到什麼。

I do want to just say, generally speaking, I think both for FCS and for SHTG, this is one of these markets where the industry, both us and Ionis, it's going to be an education market. We're going to be opening up this market. This has been -- these essentially have been almost untreatable diseases, very poorly treated diseases with available -- currently available agents that have been around for decades, mostly generic, mostly not promoted.

我只想說，一般來說，我認為對於 FCS 和 SHTG 來說，這都是一個教育市場，無論是我們還是 Ionis。我們將要開放這個市場。這些疾病基本上是無法治癒的，治療效果很差，目前可用的藥物已經存在了幾十年，而且大多是仿製藥，大多沒有被推廣。

So I'm not sure, while the Street tends to think about head-to-head, I think this is more going to be expansion. And in fact, having a couple of players in the market are going to help us expand I mean we obviously like that side-to-side comparison that Andy talked about.

所以我不確定，儘管華爾街傾向於考慮面對面的競爭，但我認為這更像是一種擴張。事實上，市場上擁有幾個參與者將會幫助我們擴張，我的意思是，我們顯然喜歡安迪談到的並排比較。

But I actually think the thing that's going to benefit the patients most here is that there's going to be 2 sets of voices out there trying to be sure that physicians get well educated about these markets understand that there are treatments now that these treatments make a difference. And I think it's probably more a question of how much the two of us can expand the pie than necessarily competing for a fixed pie. Because at this point, I don't think that's the case. So I would just add that from a medical perspective.

但實際上我認為對患者最有利的是，會有兩種聲音試圖確保醫生充分了解這些市場，並明白現在已經有治療​​方法，這些治療方法可以發揮作用。我認為這可能更多的是我們兩個人能夠把蛋糕擴大多少的問題，而不是一定要爭奪一個固定的蛋糕。因為就目前情況而言，我認為事實並非如此。所以我只是想從醫學角度補充這一點。

Then on the obesity question, the adipose question, Patrick, this is James. So the indications that we're looking at, of course, include things like obesity, Type 2 diabetes, lipodystrophy is also on the list. And we have a lot of targets that are of interest in the adiposite. Of course, we're not going to share these targets publicly at this time. I think we're evaluating those targets preclinically and you'll learn about the individual targets as they reach the clinic.

那麼關於肥胖問題，脂肪問題，派崔克，這是詹姆斯。因此，我們正在研究的適應症當然包括肥胖症、2 型糖尿病、脂肪營養障礙等。我們對脂肪沉積物有許多感興趣的目標。當然，我們目前不會公開分享這些目標。我認為我們正在臨床前評估這些目標，當它們進入臨床時您將了解各個目標的情況。

Great, thank you so much.

太好了，非常感謝。

Mayank Mamtani, B. Riley Securities.

Mayank Mamtani，B.Riley Securities。

Yeah, good afternoon. Thanks for taking our questions and, congrats on the CAA deal close. So on that, CAA partnership, maybe a couple of quick questions on AOD DM 1, You have cohorts 4 and 5 exploring 12 mg per kg quarterly and semiannual dosing.

是的，下午好。感謝您回答我們的問題，並祝賀 CAA 交易完成。因此，就 CAA 合作夥伴關係而言，也許有幾個關於 AOD DM 1 的快速問題，您有第 4 和第 5 個隊列正在探索每公斤 12 毫克的季度和半年劑量。

Just to clarify, when you have day 180 biopsy data from both cohorts 4 and 5, is that part of disclosure within this year? Or is that sort of a follow-up to initial sort of SAD early MAD update you have this year? And then similarly for ARO DUX4, which I understand is a larger study, how further would you be along in the MAD when you and your partners have done to put out an initial update this year.

需要澄清的是，當您擁有第 4 組和第 5 組的第 180 天活檢數據時，這是否屬於今年內的披露內容？或者這是今年初始 SAD 早期 MAD 更新的後續？同樣對於 ARO DUX4，據我所知這是一項更大規模的研究，當您和您的合作夥伴今年發布初步更新時，您在 MAD 方面的進展如何？

Hey Mike, so our job here is to continue these programs moving forward as quickly as we can. We think these are important drug. We look forward to handing them over to Sarepta once we finish the current studies. We really can't give you any guidance on data readouts because that's entirely up to Sarepta. We will be generating data all year when they decide to present data when data are interpretable and such, we'll be, will be really up to them, so.

嘿，麥克，我們的工作就是盡快繼續推進這些專案。我們認為這些都是重要的藥物。我們期待在完成目前的研究後將它們移交給Sarepta。我們確實無法為您提供有關數據讀數的任何指導，因為這完全取決於 Sarepta。當他們決定以可解釋的數據形式呈現數據時，我們全年都會產生數據，這將完全取決於他們。

Okay. Okay. Understood. And just a quick one on zodasiran and HoFH. Maybe if you could contrast the Phase III target patient population with that of of KSA and could patients theoretically get both anti-body and SRNA to have optimal outcomes. Thanks again for taking my question.

好的。好的。明白了。簡單介紹一下 zodasiran 和 HoFH。也許，如果您可以將 III 期目標患者群體與 KSA 的目標患者群體進行對比，那麼患者理論上是否可以同時獲得抗體和 SRNA 以獲得最佳結果。再次感謝您回答我的問題。

Yeah, I don't think that they'll be used together, and I think the target population is basically very much the AEsia target population. AISA, of course, is an intravious infusion. It has the same liability as all the monoclonal antibodies have for patients that occasionally develop severe allergic reactions, which doesn't tend to characterize the siRNAs.

是的，我認為它們不會一起使用，而且我認為目標人群基本上是 AEsia 的目標人群。當然，AISA 是一種輸注方式。它與所有單株抗體一樣，會導致患者偶爾出現嚴重的過敏反應，而 siRNA 則不會出現這種情況。

And of course, we would be quarterly dosing as opposed to monthly dosing. But I think the patient population itself, which is essentially patients that are still -- still have high LDL cholesterol despite high-dose statins and PCS inhibitors, that's basically the patient population there's a nuance there you also pick up some patients that are intolerant to statins. But essentially, the biggest part of the population of patients that despite high-dose debt and PCSK9s are still not at goal, which is basically the keys of population as well.

當然，我們會按季度給藥，而不是按月給藥。但我認為患者群體本身，本質上是那些儘管服用高劑量的他汀類藥物和 PCS 抑製劑但 LDL 膽固醇仍然較高的患者，這基本上是患者群體中的一個細微差別，你也會發現一些對他汀類藥物不耐受的患者。但本質上，大部分患者儘管服用高劑量債務和 PCSK9，仍然未達到目標，這也是患者的關鍵。

Got it. Thank you.

知道了。謝謝。

Andrea Newkirk, Goldman Sachs.

高盛的安德里亞紐柯克 (Andrea Newkirk)。

Good afternoon. Thanks so much for taking our question. Maybe a follow-up to the prior one. speak a little bit more on this decision to restart efforts with sodasterin? And maybe quantify for us the magnitude of the commercial opportunity that you do see in HoFH to justify the incremental investment that you expect to see on both the R&D as well as the commercial side. Thank you so much.

午安.非常感謝您回答我們的問題。也許是前一個的後續。您能再多談談重啟與 Sodasterin 合作的決定嗎？也許您可以為我們量化一下您在 HoFH 中看到的商業機會的大小，以證明您期望在研發和商業方面看到的增量投資是合理的。太感謝了。

Sure. So the Sarepta deal, of course, gave us capital we could we consider that opportunity. That, to us, felt like it's close to a no-brainer as exists in this industry. The data so far have been good in the clinical programs, and it was just -- it was sitting frankly, waiting for us to have the capital that we can allocate to it. Now we do.

當然。因此，Sarepta 交易當然給了我們資本，我們可以考慮這個機會。對我們來說，這感覺就像是這個行業中存在的一件不需要思考的事情。到目前為止，臨床計畫的數據都很好，只是——坦白說，它只是在等待我們擁有可以分配給它的資金。現在我們知道了。

It's not a very expensive Phase III program. It's going to be a fairly small study. It's not a gigantic market, of course. But the incremental commercial costs there are quite low because we are going to be addressing this market with plozasiran anyway. And so as I mentioned in the prepared remarks, we're almost just adding this to the bag of existing sales representatives.

這不是一個十分昂貴的第三階段計劃。這將是一項相當小規模的研究。當然，這不是一個巨大的市場。但那裡的增量商業成本相當低，因為我們無論如何都要用 plozasiran 來滿足這個市場的需求。正如我在準備好的演講中提到的那樣，我們幾乎只是將其添加到現有銷售代表的包中。

And so it doesn't cost very much more to do the Phase III. It costs almost nothing more to do the added commercial. So we just saw that as a market that we could take share. And so we plan to.

因此，第三階段的實施成本並不會提高太多。製作附加的商業廣告幾乎不會增加任何成本。因此，我們只是將其視為一個我們可以佔據份額的市場。我們計劃這麼做。

Mani Foroohar, Leerink.

Mani Foroohar，Leerink。

Hey guys, thanks for taking my question. A couple of quick ones to clarify. When you talked about your pro forma cash balance, et cetera, $1 billion, you said that was one of the things that into account was debt service, and you described is debt repayment. Are we to assume that you're going to be putting capital to paying down the 15% debt that you took out? Or should we just assume that, that is debt service in the form of interest? And then I have a follow-up.

嘿夥計們，謝謝你們回答我的問題。需要簡單澄清幾點。當您談到您的預期現金餘額等 10 億美元時，您說這是考慮的事情之一，即債務服務，而您描述的是債務償還。我們是否可以假設您將投入資本來償還您所欠的 15% 的債務？或者我們應該假設這就是以利息形式償還的債務？然後我有一個後續問題。

So we do need to make certain payments when we bring capital in from milestone payments and such. So that is included in the cash balance that I referred to earlier. And to the extent there are further milestones down the road, certain percentage of those would be considered debt repayments. But we wouldn't be making anything beyond that.

因此，當我們從里程碑付款等方式獲得資本時，我們確實需要進行某些付款。所以這包含在我之前提到的現金餘額中。如果未來還有進一步的里程碑，其中一定比例將被視為債務償還。但我們不會做任何超出這個範圍的事情。

Okay. That's helpful. And then apropos of, you the last question regarding how more capital in hand, a feeling you could sort of reinvigorate the zodasiran program for the opportunity HoHF, I want to hop back to plozasiran, how you should think about the CVOT. How do we think about potential gating to restart that timing to pursue of CVOT and how to think about your own view on what are getting events to begin such a study and the capital that you put into place and how that might affect your willingness to partner other assets to continue to keep the balance sheet for running given that, that adds meaningful OpEx?

好的。這很有幫助。然後關於您最後一個問題，關於手頭上有多少資本，您覺得可以為 zodasiran 計劃注入新活力，以獲得 HoHF 的機會，我想回到 plozasiran，您應該如何看待 CVOT。我們如何看待重新啟動追求 CVOT 時機的潛在限制，以及如何思考您對開始此類研究的事件的看法以及您投入的資本，以及這可能會如何影響您與其他資產合作以繼續保持資產負債表的運作的意願，因為這會增加有意義的營運支出？

Yeah. It's a great question. I would have, I don't have a firm answer for you other than the fact that we would like to do that CVOT, the rationale for that is clear, and I'll let Bruce expand upon that in a second. We'd like to do that. What we're waiting on is additional capital.

是的。這是一個很好的問題。我會，除了我們想做 CVOT 這一事實之外，我沒有明確的答案給你，這樣做的理由很明確，我會讓布魯斯在稍後詳細說明這一點。我們想這麼做。我們正在等待的是額外的資本。

And so we're just not prepared to start that until we've got better line of sight on additional capital to fund that. We do have a lot of capital now, that's good. but we're going to need an influx of additional capital -- substantial additional capital before we would consider starting that. I sort of listed some of the current programs that we are interested in partnering at some point, at least. Arrow rage is one.

因此，在我們找到更好的額外資金來資助該計畫之前，我們還沒有準備好開始這個計畫。我們現在確實有很多資本，這很好。但在考慮開始這項工作之前，我們需要額外的資本流入——大量的額外資本。我至少列出了一些我們有興趣在未來某個時候合作的現行項目。箭之怒就是其中之一。

We'd like to do a discovery partnership in pulmonary. We'd like to do a partnership with C3, with Factor B, with PNPLA3. We've got a number of these that are not core to our business, we're happy to let go of. We are -- and we'll see what kind of capital could come in with those. What's importantly, there are some programs that are just off limits at least for right now.

我們想在肺部領域建立探索夥伴關係。我們希望與 C3、Factor B 和 PNPLA3 建立合作夥伴關係。其中有許多並不是我們業務的核心，我們很樂意放棄它們。我們會——並且看看這些能帶來什麼樣的資本。重要的是，至少目前有一些程序是禁止的。

ALK7 and inhibit knee, we think, have too much value in them at least in the near to midterm to think about partnering. So we're just not going to do that. MAPT is another one. We're going to hold on to that at least for right now and see where that goes. We would certainly consider doing a discovery partnership in CNS with some limited number of targets.

我們認為，ALK7 和抑制膝蓋至少在近期到中期具有太大的價值，不值得考慮合作。所以我們不會這麼做。MAPT 是另一個。至少現在我們會堅持這一點，看看結果會如何。我們肯定會考慮在 CNS 中建立發現合作夥伴關係，但目標數量要有限。

Let's see if some capital comes in with that type of partnership, we could consider an -- partnership. It's not something that we're really focused on right now, but it's something that we would consider. It's not off limits like MAPT, I guess, is what I'm saying. Adipocytes, there are a ton of new targets there. We will absolutely go after some of those ourselves, and we will keep them wholly owned to expand our cardiometabolic franchise, but there's probably enough targets there for us to bring in partners as well to deteriorate new targets.

讓我們看看如果有資本透過這種類型的合作進入，我們可以考慮合作。這不是我們現在真正關注的事情，但我們會考慮。我想說的是，它並不像 MAPT 那樣是禁止進入的。脂肪細胞中有大量的新目標。我們絕對會自己去追求其中的一些，並且我們將保持對它們的全資擁有，以擴大我們的心臟代謝特許經營權，但那裡可能有足夠的目標讓我們引入合作夥伴來開發新的目標。

Cardiomyocytes that's a new space. We are not in cardiomyocytes, we are not in the clinic of cardiomyocytes right now, but we have technology that we think is pretty good and just about ready for prime time. And so that's another place that we think we can play ourselves, but also there's probably room to do some partnering there. So there's an awful lot of potential there. When we'll just see what happens.

心肌細胞這是一個新的空間。我們目前還沒有進入心肌細胞研究領域，也沒有進入心肌細胞臨床研究，但是我們認為我們的技術已經相當不錯，並且已經為黃金時段做好了準備。因此，我們認為這是我們自己可以開展業務的另一個地方，但那裡也可能有合作的空間。因此，那裡有著巨大的潛力。我們只需看看會發生什麼。

We'll see when it happens, we'll see what kind of capital comes in before we can make a decision on if and when we start that CVOT. Bruce, do you want to add anything to that?

我們將觀察它何時發生，我們將觀察有什麼樣的資本進入，然後我們可以決定是否以及何時啟動 CVOT。布魯斯，你還有什麼要補充嗎？

No. Just again for those of you who may not be up to date on the case we're doing CVOT, there's just an increasing body of information from Mendelian randomization studies, especially indicating that some of this unmet need and some of this residual risk, despite our ability to take LDLs to very, very low levels looks like from these Mendelian randomization studies, the GWAS that a significant amount of that residual risk is explainable by elevations in triglyceride-rich lipoproteins. And again, plozasiran, the strongest drug we think, has ever been seen in its ability to lower those.

不。對於那些可能不了解我們正在進行 CVOT 情況的人來說，孟德爾隨機化研究提供的信息越來越多，這些信息特別表明，儘管我們有能力將 LDL 降至非常非常低的水平，但其中一些未滿足的需求和一些殘留風險似乎仍然存在，從這些孟德爾隨機化研究和 GWAS 來看，相當一部分殘留風險可以通過富含甘油三酯的脂蛋白的升高來解釋。我們認為，plozasiran 是迄今為止降低這些濃度的最強效藥物。

And if you use the Mendelian randomization data to sort of model what you expect, there's a pretty good expectation that this could be very effective in patients with mixed hyperlipidemia and patients who severe hypertriglyceridemia kind of stays out of the chylomicronemia range, so sort of from that 500 to 800 or so milligrams per deciliter in that range we think that CVOT would have a very good chance of demonstrating substantial reduction in residual risk despite LDL being well controlled. We would like very much to do this.

如果您使用孟德爾隨機化數據對您的預期進行建模，那麼可以很好地預期，這對混合性高脂血症患者和嚴重高甘油三酯血症超出乳糜微粒血症範圍的患者非常有效，因此，在每分升 500 到 800 毫克左右的範圍內，我們認為，儘管 LDL 得到很好的控制，但 CVOT 很有可能顯著降低殘留風險。我們非常願意這麼做。

This is the drug to finally answer that question in our minds. So scientifically, this would be an extremely interesting study to cardiologists, probably not that different from how they feel about Lp(a) at this point from the standpoint of just a very, very important question to answer scientifically. So we'd love to do it, and it's just a function of being able to feel confident that we can properly fund it.

這種藥物最終可以解答我們心中的這個問題。因此從科學角度來看，這對心臟科醫生來說將是一項極其有趣的研究，從科學角度來回答這個非常非常重要的問題的角度來看，這可能與他們目前對 Lp(a) 的看法沒有太大不同。所以我們很樂意這麼做，而且我們也相信我們能夠為其提供適當的資金。

And it's also to be clear that the FHTG market alone, which, of course, would not require the CVOT, we have ongoing Phase IIIs now. We said we're going to be fully enrolled this year, we believe, and we think those studies will be finished in 2026. Those enable addressing a market that we think makes plozasiran a $2 billion to $3 billion per year drug alone. So yes, we do like the idea of continuing to expand the reach of plozasiran. But even with what we're doing right now, we think that makes plozasiran a large drug.

而且也要明確的是，光是 FHTG 市場當然不需要 CVOT，我們現在正在進行第三階段。我們說過，我們相信今年我們將全部招生，我們認為這些研究將在 2026 年完成。我們認為，這些因素能夠滿足市場需求，使得 plozasiran 成為每年價值 20 億至 30 億美元的藥物。所以是的，我們確實喜歡繼續擴大 plozasiran 的覆蓋範圍的想法。但即使以我們現在所做的努力，我們也認為 plozasiran 將成為一種重要藥物。

I'm sorry. I just want to clarify. So what I'm taking away from this is that you've given us some updated clarity on your cash position that net of sort of contractually agreed upon payments for debt service, but not including additional voluntary paydown of principal beyond that? Do you expect to have cash pro forma near the end of this year about $1 billion. Despite that, given your existing OpEx and CapEx you expect for your platform, you still need more capital to be able to feel comfortable moving forward into the CVOT.

對不起。我只是想澄清一下。所以，我從中得到的印像是，您向我們提供了有關現金狀況的最新信息，即扣除合約約定的債務償還金額，但不包括除此之外的額外自願償還的本金？您預計今年年底的現金預計約為 10 億美元嗎？儘管如此，考慮到您現有的平台營運支出和資本支出，您仍然需要更多資本才能安心地進入 CVOT。

Is that a correct interpretation of what you just said?

這是您剛才所說內容的正確解釋嗎？

Yeah. That is a correct interpretation of what I said. Because again, remember that we've got other stuff going on that we think are going to drive value as well in obesity and in the CNS and the existing SATG studies alone. So yes, those will absorb capital as well. That's why we would need additional capital to come in, in order to start a CVOT.

是的。這是對我所說內容的正確解釋。因為再一次請記住，我們還在進行其他研究，我們認為這些研究也會在肥胖症、中樞神經系統和現有的 SATG 研究方面產生價值。所以是的，這些也會吸收資本。這就是為什麼我們需要額外的資本來啟動 CVOT。

Okay, thank you for clarifying that. That was really helpful.

好的，謝謝你澄清這一點。這確實很有幫助。

Brendan Smith, TD Cowen.

布倫丹·史密斯（TD Cowen）。

Hi, great, thanks guys for taking the questions. Actually, just a really quick one on zodateran. I know you referenced a Phase III in HLF that's going to start next quarter. But given the development cost synergies that you mentioned with plozasiran and kind of the taking a look at the whole balance sheet and everything with the cardiometabolic pipeline. I'm just wondering if you have any plan to potentially pursue heterozygous FH with odastrin, like maybe if it works in HoFH or potentially simultaneously? I'm guessing that that though, or have you kind of just decided to put the idea to bet at HoFH and just kind of pursue any other indications with other drugs?

嗨，太好了，謝謝大家回答這些問題。實際上，這只是對 zodateran 的一個非常快速的介紹。我知道您提到了 HLF 的第三階段，將於下個季度開始。但考慮到您提到的與 plozasiran 的開發成本協同效應，以及對整個資產負債表和心臟代謝管道所有內容的審視。我只是想知道您是否有計劃使用 odastrin 治療雜合子 FH，例如它是否對 HoFH 有效或是否可能同時有效？我猜是這樣的，或者你只是決定把這個想法押注於 HoFH 並嘗試使用其他藥物來尋求其他適應症？

Yeah. So the I mean, we've looked at that very carefully. And we actually think that if you take the patients that receive appropriate doses of of statins and you add on to that PCSK9 inhibition, there is a persistent unmet medical need in patients that cannot get to goal inside of that HGFH market. Unfortunately, there's no regulatory pathway to actually get at those patients other than just trying to do the full development program for HGFH, Frankly, probably to include a commitment for CVOT. And we simply don't think the -- we simply don't think in that case, the juice is worth the squeeze.

是的。所以我的意思是我們已經非常仔細地研究這個問題了。我們實際上認為，如果讓患者接受適當劑量的他汀類藥物，並添加 PCSK9 抑制劑，那麼在 HGFH 市場中無法達到目標的患者將存在持續未滿足的醫療需求。不幸的是，除了嘗試為 HGFH 進行完整的開發計劃（坦白說，可能包括對 CVOT 的承諾）之外，沒有其他監管途徑可以真正接觸到這些患者。我們只是不認為——我們只是不認為在這種情況下，這樣做是值得的。

If there were a way to do a tailored program that focused on where the unmet medical need still is after PCSK9 addition to statins. That would be worth going after. But we've explored that, and there does not appear to be a regulatory path to do that. So the answer is no, we're not looking at HGFH for that reason.

如果有辦法制定一個客製化計劃，重點解決 PCSK9 和他汀類藥物聯合使用後仍未滿足的醫療需求。這是值得追求的。但我們已經探索過這一點，而且似乎沒有監管途徑可以做到這一點。所以答案是否定的，我們不是因為這個原因而研究 HGFH。

Thanks very much, guys.

非常感謝大家。

Jason Gerberry, Bank of America.

美國銀行的傑森·格貝利（Jason Gerberry）。

Hey guys, thanks for squeezing me in. For me, I'm just kind of curious how you guys are thinking about this 2- to 3-year window where you launch plozasiran for SES. And if you think that's enough time for revenues to be meaningful. And as you think about the challenge really of taking this largely undiagnosed patient group and getting them into what sounds like if you talk to clinicians, who are already prescribing [indiscernible], a small number of specialist centers to prescribe the script or if you look at it more as sort of an educational launch, and it's really all about at SHTG. Just kind of curious to get your perspective there.

嘿夥計們，感謝你們擠進我。對我來說，我只是有點好奇你們是如何考慮在這 2 到 3 年的時間內為 SES 推出 plozasiran 的。如果您認為這段時間足以讓收入變得有意義的話。當您想到真正的挑戰時，您會想到將這群大部分未確診的患者納入其中，並讓他們進入聽起來像是與已經開出 [音頻不清晰] 處方的臨床醫生交談，少數專科中心開出處方，或者如果您將其更多地視為一種教育發布，那麼這實際上就是 SHTG 的全部內容。只是有點好奇想知道你的看法。

Yeah. Thanks, Jason. This is Andy. So as I mentioned in my remarks, we're incredibly enthusiastic about plozasiran specifically for FCS patients. We do think there is a community of FCS patients who for a long time have been have not had great options for them with respect to pharmacotherapy.

是的。謝謝，傑森。這是安迪。正如我在演講中提到的，我們對 plozasiran 特別針對 FCS 患者非常熱衷。我們確實認為，FCS 患者群體長期以來在藥物治療方面一直沒有很好的選擇。

And so plavasteran being available, we think will truly be a game changer for many of these FCS patients. That's what they've told us. And so we do believe in the return on investment over the next 2 to 3 years for plozasiran and FCS specifically.

因此，我們認為普拉斯特蘭的上市將真正改變許多 FCS 患者的治療模式。他們就是這麼告訴我們的。因此，我們確實相信未來 2 到 3 年內 plozasiran 和 FCS 的投資回報。

And we're heavily focused on bringing those patients a treatment option that didn't exist previously. I would just say, as it relates to any future markets, there is a high degree of overlap, as you would know, between those physicians that will be interested in treating for SHTG versus those that will be focused on patients who have familial chylomicronemia syndrome.

我們非常致力於為這些患者提供以前不存在的治療選擇。我只想說，就任何未來市場而言，正如您所知，有興趣治療 SHTG 的醫生與專注於家族性乳糜微粒血症綜合症患者的醫生之間存在高度重疊。

So any medical and commercial-related activities conducted over the next 2 to 3 years, focused on FCS. No doubt, there'll be an overlap of those physicians that will be interested in understanding that therapy for patients who have SHTG as well.

因此，未來 2 到 3 年開展的任何醫療和商業相關活動都將集中在 FCS 上。毫無疑問，這些醫生對了解 SHTG 患者的治療方法也會感興趣。

Got it. Thanks.

知道了。謝謝。

And that does conclude today's Q&A session. Now I'd like to go ahead and turn the call back over to Chris for closing remarks. Please go ahead.

今天的問答環節到此結束。現在我想將電話轉回給克里斯，請他作最後發言。請繼續。

Thanks everyone for joining us today and we look forward to seeing you next quarter.

感謝大家今天的加入，我們期待下季再見你們。

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

今天的電話會議到此結束。感謝您的加入。您現在可以斷開連線。