Arrowhead Pharmaceuticals Inc (ARWR) 2025 Q2 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。（操作員指示）

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

現在，我將會議交給 Arrowhead 投資人關係副總裁 Vince Anzalone。請繼續，文斯。

Thank you, and good afternoon, everyone. Thank you for joining us today to discuss Arrowhead's results for its fiscal 2025 second quarter ended March 31, 2025. With us today from management are President and CEO, Dr. Chris Anzalone, who will provide an overview; Dr. Bruce Gibbon, 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; Dr. James Hamilton, Chief Medical Officer and Head of R&D, who will discuss our earlier-stage development programs; and Ken Myszkowski, our outgoing Chief Financial Officer, who is retiring this week, who will give a review of the financials. We also welcome Dan Apel, our incoming CFO, who is also with us on the call today.

謝謝大家，下午好。感謝您今天加入我們，討論 Arrowhead 截至 2025 年 3 月 31 日的 2025 財年第二季業績。今天與我們一起出席的管理層有總裁兼首席執行官 Chris Anzalone 博士，他將進行概述；臨時首席醫學科學家 Bruce Gibbon 博士將提供有關我們心臟代謝管道的最新進展；安迪戴維斯 (Andy Davis)，高級副總裁兼全球心臟代謝特許經營負責人；誰將提供商業化活動的最新情況？首席醫療官兼研發主管 James Hamilton 博士將討論我們早期階段的開發計劃；我們的財務長 Ken Myszkowski 將於本週退休，他將對財務狀況進行審查。我們也歡迎即將上任的財務長 Dan Apel，他也參加了今天的電話會議。

Following management's prepared remarks, we will open 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 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, please refer to our SEC filings, including our most recent annual report on Form 10-K, and our quarterly reports on Form 10-Q.

在管理階層發表完準備好的發言後，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 條所定義範圍內的某些前瞻性陳述。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。有關這些風險的更多詳細信息，請參閱我們向美國證券交易委員會 (SEC) 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 Chris Anzalone, President and CEO of the company. Chris?

現在我想將電話轉給公司總裁兼執行長 Chris Anzalone。克里斯？

Thanks, Vince. Good afternoon, everyone, and thank you for joining us today. Before I start, I want to say thank you to Ken and wish him the best in his retirement. Ken has been a valuable member of the Arrowhead team, and he retires at a time of great financial strength for the company. The finance organization that Ken built over the years is very capable and provides strong support to our ambitious development and commercialization plans. From all of us at Arrowhead, thank you for all the important contributions over the last 16 years.

謝謝，文斯。大家下午好，感謝大家今天的參與。在開始之前，我想向肯表示感謝，並祝他退休後一切順利。Ken 一直是 Arrowhead 團隊的寶貴成員，他在公司財務狀況良好時退休。Ken 多年來建立的金融機構非常有能力，為我們雄心勃勃的發展和商業化計劃提供了強有力的支持。我們 Arrowhead 全體人員感謝您在過去 16 年裡所做的所有重要貢獻。

I'm also excited that Dan Apel will join us as our new CFO at a critical time for Arrowhead. We expect to make the transition from development stage to commercial stage with the planned launch of plozasiran this year, pending regulatory review and approval. Dan is an accomplished pharmaceutical executive who can make an immediate and important impact on our business.

我也很高興 Dan Apel 將在 Arrowhead 的關鍵時刻加入我們，擔任新任財務長。我們預計，隨著今年計劃推出的 plozasiran 的上市，我們將從開發階段過渡到商業階段，等待監管部門的審查和批准。丹是一位經驗豐富的製藥業主管，他可以對我們的業務產生直接而重要的影響。

Let's now talk about our business and the progress we've made toward our short-, mid- and long-term goals. Arrowhead is at an important point, both in terms of capabilities and potential value as we drive our organization toward our first commercial launch, which we anticipate this year. Following this, we expect multiple additional independent and partner launches over the next few years.

現在讓我們來談談我們的業務以及我們在實現短期、中期和長期目標方面所取得的進展。無論從能力或潛在價值來看，Arrowhead 都處於一個重要的節點，我們正在推動組織實現首次商業發布，預計今年即可實現。在此之後，我們預計未來幾年將有多個獨立和合作夥伴推出新產品。

The combination of commercial expansion, our extraordinarily productive discovery engine, the increasingly validated nature of our platforms and RNAi modality, our large pipeline of clinical stage assets, our strong balance sheet, and clear access to additional nondilutive capital together provide us with a level of upside potential and stability that I believe rarity in our industry. This is always attractive, but is even more valuable at a time when biotech markets have been depressed for the past several years and the near-term capital markets are uncertain at best.

商業擴張、我們極其高效的發現引擎、我們平台和 RNAi 模式日益得到驗證的性質、我們龐大的臨床階段資產管道、我們強勁的資產負債表以及清晰的額外非稀釋性資本獲取渠道，這些因素共同為我們提供了一定程度的上行潛力和穩定性，我相信這在我們的行業中是罕見的。這始終很有吸引力，但在過去幾年生物技術市場低迷、短期資本市場充滿不確定性的時期，這更有價值。

As the current biotech market weakness causes people to weigh the trade-off of stability versus the potential for explosive value growth, I think we have the tools for both. I view our value proposition in layers.

由於當前生物技術市場的疲軟導致人們權衡穩定性與爆炸性價值成長潛力之間的權衡，我認為我們擁有兩者的工具。我從多個層面來看我們的價值主張。

Layer 1 is plozasiran, constitutes our primary near- and midterm value driver and provides a strong base for us. Plozasiran has shown to be a potent triglyceride-lowering agent across multiple clinical studies in hundreds of patients. We believe there are 3 million to 4 million people in the US alone who suffer from severe hypertriglyceridemia, or SHTG, as defined by fasting triglyceride levels above 500 milligrams per deciliter. We are preparing to launch into a small subgroup of this population, patients with familial chylomicronemia syndrome, or FCS, and have a PDUFA date of November 18, 2025.

第 1 層是 plozasiran，構成我們主要的近期和中期價值驅動因素，並為我們提供了堅實的基礎。針對數百名患者的多項臨床研究已證明 Plozasiran 是一種有效的降低三酸甘油酯的藥物。我們認為，光在美國就有 300 萬至 400 萬人患有嚴重高三酸甘油脂血症（SHTG），其定義為空腹三酸甘油酯水平超過每分升 500 毫克。我們正準備將研究範圍擴大到該族群的一小部分，即家族性乳糜微粒血症症候群（FCS）患者，其 PDUFA 日期為 2025 年 11 月 18 日。

We also completed the submission of a marketing authorization application or MAA with the EMA and are working through additional planned submissions in other select geographies.

我們也完成了向 EMA 提交行銷授權申請或 MAA，並且正在其他選定地區進行其他計畫提交。

The Phase 3 data supporting our regulatory submissions were consistent and encouraging. Genetically defined and clinically defined FCS patients responded similarly with reductions in triglycerides of about 80% from baseline. Approximately 75% and 50% of patients with had triglycerides go below 880 and 500 milligrams per deciliter, respectively, which are discussed in guidelines and the academic literature as important goals for minimizing pancreatitis risk. These are truly impressive levels to achieve in FCS patients as the mean baseline triglyceride level in the study was approximately 2,500 milligrams per deciliter. Plozasiran was generally well tolerated and showed triglyceride reductions in 100% of patients treated at the primary endpoint of 10 months.

支持我們監管提交的第三階段數據是一致且令人鼓舞的。基因定義和臨床定義的 FCS 患者的反應相似，三酸甘油酯從基線降低約 80%。大約 75% 和 50% 的患者的三酸甘油酯分別低於每分升 880 和 500 毫克，這在指南和學術文獻中被討論為最大限度降低胰臟炎風險的重要目標。對於 FCS 患者來說，達到這樣的水平確實令人印象深刻，因為研究中的平均基線三酸甘油酯水平約為每分升 2,500 毫克。Plozasiran 整體耐受性良好，在 10 個月的主要終點，接受治療的患者中 100% 的三酸甘油酯均降低。

Our hope of treating FCS patients is important. This is a historically underserved population, and we believe plozasiran could be an important medicine for them. However, we view this as just the beginning. SHASTA-3, SHASTA-4, and MUIR-3 are Phase 3 studies designed to support a supplemental NDA and other applications on a global basis to enable us to treat a broader SHTG population. These studies are moving rapidly, and we believe they could be fully enrolled this summer.

我們對治療 FCS 患者的希望是巨大的。這是一個歷史上未得到充分服務的群體，我們相信 plozasiran 可以成為他們的重要藥物。然而，我們認為這只是一個開始。SHASTA-3、SHASTA-4 和 MUIR-3 是第 3 階段研究，旨在支持補充 NDA 和其他全球應用，使我們能夠治療更廣泛的 SHTG 族群。這些研究進展迅速，我們相信今年夏天就能全部招滿。

We are also in the process of initiating SHASTA-5, which is an outcome study, to specifically evaluate the risk reduction of acute pancreatitis in high-risk patients with SHTG. We think this is an innovative strategy to potentially demonstrate meaningful value for patients, physicians, and payers.

我們也正在啟動一項結果研究 SHASTA-5，專門評估 SHTG 高風險患者急性胰臟炎風險的降低情況。我們認為這是一種創新策略，可能為患者、醫生和付款人帶來有意義的價值。

Our second layer of value may be our initial obesity candidates and initial CNS. Regarding the former, ARO-INHBE is currently dosing in obese patients, and we expect ARO-ALK7 to begin dosing in obese patients shortly. Both are designed to intervene in a biological pathway regulating fat storage. ARO-INHBE targets hepatocytes with the same TRiM platform used in several ongoing clinical studies and have been in thousands of patients. It is designed to reduce hepatocyte expression of Activin E, which is a ligand for adipose ALK7.

我們的第二層價值可能是我們最初的肥胖候選人和最初的中樞神經系統。對於前者，ARO-INHBE 目前正在對肥胖患者進行給藥，我們預計 ARO-ALK7 很快就會開始對肥胖患者進行給藥。兩者均旨在介入調節脂肪儲存的生物途徑。ARO-INHBE 採用與正在進行的多項臨床研究中使用的 TRiM 平台相同的方式靶向肝細胞，並且已在數千名患者身上進行試驗。它旨在減少肝細胞中 Activin E 的表達，Activin E 是脂肪 ALK7 的配體。

ARO-ALK7 is the first adipocyte-targeted siRNA with a new TRiM platform that in animal models has shown good uptake in adipose tissue and high levels of target gene knockdown with a long duration of effect that may enable Q4 month, Q6 month, or less frequent administration. ARO-ALK7 is designed to reduce expression of the ALK-7 receptor itself in adipose tissue.

ARO-ALK7 是第一個具有新 TRiM 平台的針對脂肪細胞的 siRNA，在動物模型中已顯示出在脂肪組織中良好的吸收和高水平的目標基因敲低，並且具有較長的效果，可以實現每 4 個月、每 6 個月或更低頻率的給藥。ARO-ALK7 旨在減少脂肪組織中 ALK-7 受體本身的表達。

Both programs demonstrated substantial reductions in visceral fat versus control while simultaneously preserving lean mass in animal models. Both targets are also supported by human genetics, where loss of function carriers have favorable body composition and metabolic characteristics compared to noncarriers without any apparent safety cost.

這兩個項目都表明，與對照組相比，內臟脂肪顯著減少，同時在動物模型中維持了瘦體重。這兩個目標也得到了人類遺傳學的支持，其中功能喪失的攜帶者與非攜帶者相比具有良好的身體組成和代謝特徵，並且沒有任何明顯的安全成本。

It's a very intriguing pathway that we believe may fill some important gaps left by standard of care obesity treatments addressing some of the shortcomings of the GLP-1/GIP class. The possibility of long-acting agents that are well tolerated, spare muscle mass and enable visceral fat loss without dependence on restriction to site.

這是一個非常有趣的途徑，我們相信它可以填補標準肥胖症治療留下的一些重要空白，解決 GLP-1/GIP 類的一些缺點。長效藥物具有良好的耐受性，可以節省肌肉質量，並且可以減少內臟脂肪，而無需依賴對部位的限制。

ARO-INHBE began dosing a Phase 1/2 study in December 2024, and we anticipate having some initial data by the end of 2025. As I mentioned, we expect ARO-ALK7 to begin dosing shortly, and we should have some initial data soon after ARO-INHBE results become available. Studies in both candidates include single dose and multiple dose monotherapy arms in obese subjects as well as multiple dose arms that include combination with tirzepatide.

ARO-INHBE 於 2024 年 12 月開始進行 1/2 期研究，我們預計到 2025 年底將獲得一些初步數據。正如我所提到的，我們預計 ARO-ALK7 將很快開始給藥，並且在 ARO-INHBE 結果公佈後我們應該很快就會得到一些初步數據。兩種候選藥物的研究包括肥胖受試者的單劑量和多劑量單一療法組以及與 tirzepatide 聯合使用的多劑量療法組。

Our CNS BBB platform has made great strides in recent years. We have a substantial amount of preclinical data across multiple animal models that make us optimistic that we can deliver potent RNAi drugs to the brain via a simple subcutaneous injection. Delivering large molecule drugs systemically and getting past the blood-brain barrier has been a holy grail virtually as long as complex biological drugs have been developed, and we expect to be in the clinic late this year.

我們的 CNS BBB 平台近年來取得了長足的進步。我們擁有大量跨多種動物模型的臨床前數據，這讓我們樂觀地認為，我們可以透過簡單的皮下注射將強效的 RNAi 藥物輸送到大腦。自從複雜的生物藥物被開發以來，系統性地輸送大分子藥物並穿過血腦屏障一直是一個難題，我們預計該藥物將在今年稍後進入臨床階段。

Our first candidate, ARO-MAPT, targets the tau protein for potential treatment of Alzheimer's. We expect to follow that with ARO-HTT, licensed to Sarepta, against Huntington's disease by the end of the year.

我們的第一個候選藥物 ARO-MAPT 針對 tau 蛋白，有望用於治療阿茲海默症。我們預計，到今年年底，ARO-HTT 將獲得 Sarepta 的許可，用於治療亨廷頓舞蹈症。

In the first half of 2026, we expect to bring ARO-SNCA to the clinic, which targets alpha-synuclein for potential treatment of Parkinson's. These are all well-validated targets against very important diseases for which effective agents have long been sought, and we look forward to seeing how they translate from animals to humans.

2026 年上半年，我們預計將 ARO-SNCA 引入臨床，該藥物針對 α-突觸核蛋白，有望用於治療帕金森氏症。這些都是針對非常重要的疾病的經過充分驗證的目標，人們長期以來一直在尋找有效的藥物，我們期待看到它們如何從動物轉化為人類。

A third layer of value could come from our other Phase 3 drugs. We expect to begin enrolling a year-long Phase 3 study of zodasiran for homozygous familial hypercholesterolemia, or HoFH shortly. The HoFH patients treated with zodasiran in Phase 1 and Phase 2 studies give us confidence that they may have a potent LDL-C lowering agent that only requires quarterly dosing in this important at-risk patient population. The sales infrastructure we are building for plozasiran could easily be leveraged to this population. So this feels like a straightforward, relatively rapid, low-risk, and low-cost expansion of our commercial presence.

第三層價值可能來自我們的其他 3 期藥物。我們預計很快就會開始招募為期一年的 zodasiran 治療純合性家族性高膽固醇血症 (HoFH) 的 3 期研究。在第 1 階段和第 2 階段研究中接受 zodasiran 治療的 HoFH 患者讓我們相信，他們可能擁有一種強效的 LDL-C 降低藥物，並且對於這一重要的高風險患者群體來說，只需每季度服用一次。我們為 plozasiran 建造的銷售基礎設施可以輕鬆地惠及這一人群。因此，這感覺就像是我們商業影響力的一次直接、相對快速、低風險、低成本的擴張。

Fazirsiran is our drug candidate against AAT liver disease. Our prior studies give us confidence that it could be an effective agent to reverse fibrosis in this largely unserved patient population. Fazirsiran is partnered with Takeda, and they have publicly guided the Phase 3 studies could complete enrollment this year. They are two-year studies to primary endpoint.

Fazirsiran 是我們針對 AAT 肝病的候選藥物。我們先前的研究讓我們相信它可以成為逆轉這一大部分未治療的患者群體的纖維化的有效藥物。Fazirsiran 與武田製藥合作，雙方已公開指示第三階段研究可在今年完成招募。這是一項為期兩年、針對主要終點的研究。

While this is partnered, our economics are substantial with 50/50 profit share in the US, 20%, 25% royalties ex US, and up to $527 million of remaining milestones. While we view these as our primary near- and midterm value drivers, there are substantial pieces of our business underneath them, providing redundancy and additional upside potential. They include four wholly owned additional Phase 2-ready clinical programs in ARO-C3, ARO-CFB, ARO-RAGE, and ARO-PNPLA3.

雖然是合作關係，但我們的經濟效益相當可觀，在美國，利潤分成比例為 50/50，美國以外，特許權使用費為 20%，剩餘里程碑金額高達 5.27 億美元。雖然我們將這些視為我們的主要近期和中期價值驅動因素，但在它們之下還有大量業務，可提供冗餘和額外的上行潛力。其中包括 ARO-C3、ARO-CFB、ARO-RAGE 和 ARO-PNPLA3 四個全資擁有的額外 2 期臨床項目。

Two Phase 2 programs partnered with GSK against chronic hepatitis B infection and MASH, another Phase 3 program partnered with Amgen in olpasiran, four Phase 1/2 clinical programs partnered with Sarepta, three designated preclinical programs partnered with Sarepta, one of which I already mentioned in HTT, and six additional preclinical programs to be named by Sarepta. And of course, underlying all of this is a discovery engine that we believe is second to none in the siRNA field. We expect this to continue to drive value as a basis for many additional wholly owned drugs and through future partnerships.

兩個 2 期項目與 GSK 合作，針對慢性乙型肝炎感染和 MASH，另一個 3 期項目與 Amgen 合作，針對奧帕西蘭，四個 1/2 期臨床項目與 Sarepta 合作，三個指定的臨床前項目與 Sarepta 合作，其中一個我已經在 HTT 中提到過，另外六個臨床前項目將由 Sarepta 命名。當然，所有這一切的背後是一個我們認為在 siRNA 領域首屈一指的發現引擎。我們預計這將繼續推動價值，作為許多其他全資藥品和未來合作夥伴關係的基礎。

With all these layers, one can reasonably ask how many of these would be required to create a large, productive, sustainable pharmaceutical company. We indeed have many opportunities to create durable value. Importantly, we believe we have the capital and access to substantial additional capital to support our work. The Sarepta deal was a critical component of this.

考慮到所有這些層面，人們不禁要問，需要多少個層面才能創造一個大型、高效、永續發展的製藥公司。我們確實有很多機會創造持久價值。重要的是，我們相信我們擁有資本，並且可以獲得大量額外資本來支持我們的工作。Sarepta 交易是其中的關鍵組成部分。

During the last quarter, we closed the global license and collaboration agreement with Sarepta Therapeutics, materially strengthening our balance sheet. This transaction brought in $500 million as an upfront payment and $325 million through the purchase by Sarepta of Arrowhead common stock at $27.25 per share. Arrowhead will also receive $250 million to be paid in annual installments of $50 million over five years.

上個季度，我們與 Sarepta Therapeutics 達成了全球許可和合作協議，大大增強了我們的資產負債表。這筆交易帶來了 5 億美元的預付款以及 3.25 億美元的 Sarepta 以每股 27.25 美元的價格收購 Arrowhead 普通股的收入。Arrowhead 還將獲得 2.5 億美元，分五年每年支付 5,000 萬美元。

In the short term, we have potential to receive an additional $300 million in milestone payments associated with the continued enrollment of the Phase 1/2 study of ARO-DM1, which we are on track to achieve during the next few quarters. Taken together, this adds up to $1.375 billion in cash payments. The total potential value of this deal, including upfront payments, equity investments, and potential milestones exceeds $11 billion. We are also eligible to receive tiered royalties on commercial sales. This will be a transformational deal in any environment.

短期內，我們有可能獲得與繼續進行 ARO-DM1 第 1/2 階段研究相關的額外 3 億美元里程碑付款，我們預計在未來幾季內實現這一目標。加起來，現金支付總額高達 13.75 億美元。包括預付款、股權投資和潛在里程碑付款在內的這筆交易的總潛在價值超過 110 億美元。我們還有資格獲得商業銷售的分級版稅。無論在何種環境下，這都將是一項變革性的協議。

As I mentioned, with the state of biotech equity markets today, we feel very good about not having to raise equity capital at this time to fund our growth as we become a commercial company. We are now funded into 2028 and through multiple important milestones that we think can drive substantial value for our shareholders.

正如我所提到的，考慮到當今生技股票市場的狀況，我們很高興目前不必籌集股本來為我們成為一家商業公司的成長提供資金。我們現在已經獲得了到 2028 年的資金，並將實現多個重要里程碑，我們認為這些里程碑可以為股東帶來巨大的價值。

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

了解上述概述後，我現在想將電話交給 Bruce Given。布魯斯？

Thanks, Chris, and good afternoon, everyone. Arrowhead has been working in RNAi interference for nearly 20 years. During that time, we have made great strides creating a modality that is increasingly scalable, reliable, potent, and generally well-tolerated. We've also made great strides bringing RNAi to where it is needed.

謝謝，克里斯，大家下午好。Arrowhead 在 RNAi 幹擾領域工作近 20 年。在此期間，我們取得了長足的進步，創造了一種可擴展性越來越強、可靠、有效且普遍耐受性良好的治療模式。我們在將 RNAi 應用於需要的地方方面也取得了巨大進步。

In addition to delivering it to hepatocytes, we are now able to address lung, CNS, muscle, adipose, and cardiomyocytes. We have always been a great R&D platform company, and we are now taking a next step forward as we seek our first marketing approval for plozasiran in familial chylomicronemia syndrome or FCS.

除了將其輸送至肝細胞外，我們現在還可以處理肺部、中樞神經系統、肌肉、脂肪和心肌細胞。我們一直是一家優秀的研發平台公司，現在我們正在邁出下一步，尋求 plozasiran 在家族性乳糜微粒血症症候群 (FCS) 中的首次上市批准。

Most of you will be aware of the results of our Phase 3 PALISADE study, which was published in the New England Journal of Medicine last year and showed statistically significant responses on all primary and alpha-controlled secondary endpoints, including a large reduction in the primary endpoint of triglyceride reduction of 10 months as well as reduction in incidence of confirmed pancreatitis in the protocol-defined comparison of placebo and the combined 25- and 50-milligram dose groups.

大多數人可能都知道我們第三階段 PALISADE 研究的結果，該研究於去年發表在《新英格蘭醫學雜誌》上，並顯示在所有主要終點和 α 控制的次要終點上均有統計學上顯著的反應，包括主要終點甘油三酯降低 10 個月的大幅減少，以及在方案定義的安慰劑組和合併 25 毫克和 50 毫克發病率的比較中。

Following pre-NDA discussions with the FDA, a marketing application for approval for use in SCS was submitted on November 16, 2024, and accepted for review by FDA with a PDUFA date of November 18, 2025. At this time, we do not anticipate being asked to participate in an advisory committee meeting. We have been asked frequently whether the changes in Washington have impacted the review. While we have no special insights into the inner workings of the agency, our impression has been that the review is progressing as we would have anticipated, and we know of no FDA personnel or timing changes affecting our program at this time.

在與 FDA 進行 NDA 前討論後，於 2024 年 11 月 16 日提交了 SCS 的行銷申請，並獲得 FDA 接受審查，PDUFA 日期為 2025 年 11 月 18 日。目前，我們預計不會被要求參加諮詢委員會會議。我們經常被問到華盛頓的變化是否影響了審查。雖然我們對該機構的內部運作沒有特別的了解，但我們的印像是，審查正在按照我們預期的方式進行，我們目前還不知道 FDA 人員或時間變化會影響我們的計劃。

We have also had routine prefiling meetings with EMA and appointed CHMP rapporteurs that culminated in the submission of a marketing authorization application, or MAA, on February 28, 2025, which was confirmed to be valid for review on March 20, 2025. Our plan is to seek approval in the UK following approval in either the US or Europe by leveraging the International Recognition Procedure.

我們也與 EMA 和指定的 CHMP 報告員舉行了例行預備會議，最終於 2025 年 2 月 28 日提交了上市許可申請 (MAA)，並確認該申請將於 2025 年 3 月 20 日生效以供審查。我們的計劃是利用國際認可程序，在美國或歐洲獲得批准後，尋求在英國獲得批准。

We've also had prefiling meetings with the Canadian and Japanese regulatory authorities and have plans for filing marketing applications in those and other jurisdictions as well. We are hopeful that these filings will lead to Arrowhead's first commercial launch, possibly beginning as early as late this year.

我們也與加拿大和日本的監管機構舉行了預備會議，並計劃在這些司法管轄區和其他司法管轄區提交行銷申請。我們希望這些申請將促成 Arrowhead 的首次商業發射，最快可能在今年年底開始。

As welcome as we believe that plozasiran will be for FCS patients, this is just the beginning of the story for this important drug. While we were studying plozasiran in SCS, we are also evaluating the drug in much larger patient populations, including severe hypertriglyceridemia, or SHTG, defined as patients with fasting triglycerides above 500 milligrams per deciliter but without genetic FCS, as well as in patients with mixed hyperlipidemia. These important studies led to publications last year in the New England Journal of Medicine, JAMA Cardiology, and Circulation journals.

儘管我們相信 plozasiran 將受到 FCS 患者的歡迎，但這只是這個重要藥物故事的開始。在我們研究 plozasiran 對 SCS 的作用的同時，我們也在更大的患者群體中評估該藥物，包括嚴重高甘油三酯血症 (SHTG)，定義為空腹甘油三酯超過 500 毫克/分升但沒有遺傳性 FCS 的患者，以及混合性高脂血症患者。這些重要的研究成果於去年在《新英格蘭醫學雜誌》、《JAMA心臟病學》和《循環》雜誌上發表。

After receiving end of Phase 2 feedback from FDA and EMA, we have initiated a Phase 3 program in severe hypertriglyceridemia. This program is designed to meet key standards based on guidance documents from the International Council for Harmonisation. Key requirements that drove design considerations include two pivotal placebo-controlled trials in SHTG patients and a safety database of at least 1,500 patients treated with plozasiran compared with placebo for 12 months.

在收到 FDA 和 EMA 的第 2 階段結束回饋後，我們啟動了針對嚴重高三酸甘油酯血症的第 3 階段計畫。該計劃旨在滿足國際協調理事會指導文件的關鍵標準。推動設計考量的關鍵要求包括對 SHTG 患者進行兩項關鍵的安慰劑對照試驗，以及一個包含至少 1,500 名接受 plozasiran 治療與接受安慰劑治療 12 個月患者的安全性資料庫。

Hence, SHASTA-3 and 4 are similar studies designed to demonstrate statistically significant improvement in triglycerides with 25 milligrams plozasiran compared to placebo over 12 months of treatment. The two trials total around 700 patients and are very highly powered, given the results seen in the Phase 2 SHASTA-2, where the primary endpoint of difference in triglycerides at a week 24 compared to baseline at the 25-milligram dose was negative 53% with a p-value of 0.0001. To reach the necessary 1,500 patients for the safety database, SHASTAS 3 and 4 are supplemented by a supportive MUIR-3 trial in mixed hyperlipidemia, also blinded and comparing 25 milligram quarterly plozasiran versus placebo for one year with a planned enrollment of approximately 1,400 patients.

因此，SHASTA-3 和 4 是類似的研究，旨在證明與安慰劑相比，經過 12 個月的治療，25 毫克 plozasiran 可顯著改善三酸甘油酯水平。這兩項試驗總共涉及約 700 名患者，根據第 2 階段 SHASTA-2 的結果，這兩項試驗的功效非常強，其中，25 毫克劑量下第 24 週甘油三酯與基線相比的差異的主要終點為負 53%，p 值為 0.0001。為了達到安全資料庫所需的 1,500 名患者，SHASTAS 3 和 4 補充了針對混合性高脂血症的支持性 MUIR-3 試驗，該試驗也採用盲法，比較每季度服用 25 毫克 plozasiran 與服用安慰劑一年的效果，計劃招募約 1,400 名患者。

We have previously guided that we expect the last patient to be randomized in the SHTG program this year. Based on enrollment to date, we now anticipate the last patient to enroll sometime this summer. We've been encouraged by the enthusiasm of our investigators as indicated by the rapid enrollment and also by a very low premature discontinuation rate for adverse events and other reasons. The last patient entered will be treated for one year before the database can be locked, the data analyzed, and hopefully, submissions made to regulatory authorities seeking approval for use in SHTG patients. Thus, before the end of the summer, it should be possible to narrow the potential timing for SHTG supplemental NDA submission.

我們之前曾指導過，預計今年最後一位患者將在 SHTG 計畫中隨機分組。根據迄今為止的入院情況，我們預計最後一位患者將於今年夏天的某個時候入院。我們研究人員的熱情令我們感到鼓舞，這體現在快速的招募以及因不良事件和其他原因而導致的過早停藥率非常低。最後一位輸入的患者將接受一年的治療，然後資料庫才會被鎖定，數據才會被分析，並且預計將提交給監管機構，尋求批准用於 SHTG 患者。因此，在夏季結束之前，應該可以縮短 SHTG 補充 NDA 提交的潛在時間。

The SHTG program also features a first-of-kind study named SHASTA-5 to directly assess the ability of plozasiran to reduce the risk of acute pancreatitis in SHTG patients with a purpose-designed outcome study. We are conducting the study expressly to meet the needs of sophisticated payers, especially outside of the US.

SHTG 計畫也進行了一項名為 SHASTA-5 的首創研究，透過專門設計的結果研究直接評估 plozasiran 降低 SHTG 患者急性胰臟炎風險的能力。我們進行這項研究是為了滿足成熟付款人的需求，尤其是美國以外的付款人的需求。

It is not needed for the SHTG filing and is unlikely to be completed prior to the submission. We do hope that will be completed during the review process in Europe and elsewhere available pricing discussions with national payors post-approval. We cannot provide precise timing of not only because of uncertain time of enrollment, but also as an outcome study, treatment will continue until the required number of events have been collected rather than for a fixed duration. Screening is underway at canters currently open for enrollment, so the trial is underway. More information on design will be presented following presentation at major medical meeting.

它對於 SHTG 備案來說不是必需的，並且不太可能在提交之前完成。我們確實希望這將在歐洲和其他地方的審查過程中完成，並在批准後與國家付款人進行定價討論。我們無法提供精確的時間，不僅因為入學時間不確定，而且作為一項結果研究，治療將持續到收集到所需數量的事件，而不是固定的持續時間。目前開放招生的中心正在進行篩選，因此試驗正在進行中。有關設計的更多資訊將在主要醫學會議上發表後公佈。

The R&D group is also playing its role in growing the awareness that new treatments are reaching the market for treating FCS. Our medical affairs team reporting into R&D continues to play a vital role in educating the medical community.

研發團隊也正在提高人們對治療 FCS 的新療法正在進入市場的認識方面發揮作用。我們的醫療事務團隊負責研發報告，在教育醫學界方面繼續發揮至關重要的作用。

Our medical science liaisons are actively engaging healthcare professionals in scientific exchange, helping them better understand and raising awareness of familial chylomicronemia syndrome, the significant unmet medical need, and the growing body of clinical data now available.

我們的醫學科學聯絡員正在積極與醫療保健專業人員進行科學交流，幫助他們更好地理解和提高對家族性乳糜微粒血症綜合症、重大未滿足的醫療需求以及日益增多的臨床數據的認識。

The team has been present at key medical congresses during this last quarter, including the American College of Cardiology meeting, the European Atherosclerosis Society and British Atherosclerosis Society joint meeting, and the European Society of Endocrinology meeting taking place presently.

該團隊參加了最近一個季度的重要醫學會議，包括美國心臟病學會會議、歐洲動脈粥狀硬化學會和英國動脈粥狀硬化學會聯合會議以及正在舉行的歐洲內分泌學會會議。

In parallel, our publications team continues to generate and disseminate important data to support these scientific efforts and expand awareness within the clinical community. Most recently at EAS, an abstract authored by experts in the field titled, PALISADE: Plozasiran Decreases Risk of Acute Pancreatitis and Improves Indices of Quality of Life in FCS, was featured. The authors concluded in the abstract that in patients with FCS, plozasiran markedly reduced triglycerides and risk of pancreatitis with promising changes in indices of quality of life.

同時，我們的出版團隊繼續產生和傳播重要數據，以支持這些科學努力並擴大臨床界的認識。最近，在 EAS 上，一篇由該領域專家撰寫的摘要被重點介紹，題為「PALISADE：Plozasiran 降低急性胰臟炎風險並改善 FCS 的生活品質指數」。作者在摘要中得出結論，對於 FCS 患者，plozasiran 顯著降低了三酸甘油酯和胰臟炎風險，生活品質指標發生了可喜的變化。

Those of you who have watched us for a while know that we have another agent in our cardiometabolic pipeline that like plozasiran, has very strong support from human genetics. I'm describing zodasiran, an RNAi drug designed to reduce expression of angiopoietin protein like 3 or ANGPTL3. This drug also produced strong results in two Phase 2s, including ARCHES-2 in mixed hyperlipidemia, also published in the New England Journal of Medicine, as well as the GATEWAY study in HoFH patients with data presented last week at the European Atherosclerosis Society Conference. However, as we've discussed previously, we saw zodasiran as positioned in the crowded LDL space where the unmet medical need has largely been addressed by statins and PCSK9 inhibitors.

那些關注我們一段時間的人知道，我們的心臟代謝產品線中還有另一種藥物，它和 plozasiran 一樣，得到了人類遺傳學的大力支持。我正在描述 zodasiran，一種旨在減少血管生成素蛋白 3 或 ANGPTL3 表達的 RNAi 藥物。這款藥物也在兩項 2 期臨床試驗中取得了優異的成果，包括針對混合性高脂血症的 ARCHES-2 研究（該研究也發表在《新英格蘭醫學雜誌》上），以及針對 HoFH 患者的 GATEWAY 研究（該研究的數據於上週在歐洲動脈粥樣硬化學會會議上公佈）。然而，正如我們之前所討論過的，我們認為 zodasiran 定位於擁擠的 LDL 領域，其中未滿足的醫療需求已主要透過他汀類藥物和 PCSK9 抑制劑得到解決。

But there is an important population when we think zodasiran would make an important contribution without requiring an outsized commitment of resources by Arrowhead. This being for patients with homozygous familial hypercholesterolemia. These patients have exceptionally high LDL cholesterol levels. And because their genetic abnormalities usually result in very low or absent LDL receptor function are usually not able to get to goal LDL levels even with maximal statin and PCSK9 therapy. This leaves them with very high risk of suffering cardiovascular events and early mortality.

但是，當我們認為 zodasiran 能夠做出重要貢獻而不需要 Arrowhead 投入過多的資源時，就會出現一個重要的人口群體。這適用於患有純合家族性高膽固醇血症的患者。這些患者的低密度脂蛋白膽固醇水平極高。而且由於他們的基因異常通常會導致 LDL 受體功能非常低或缺失，即使採用最大劑量的他汀類藥物和 PCSK9 治療通常也無法達到目標 LDL 水平。這使他們罹患心血管疾病和過早死亡的風險非常高。

Monoclonal antibody against ANGPTL3 has already been proven effective in these patients, but requires monthly intravenous infusions and can lead to immunologic reactions. We conducted an exploratory Phase 2 study in this population and saw similar benefit but with convenient quarterly subcutaneous dosing. Moreover, these patients are usually cared for by physicians, which largely overlap the physicians who treat FCS and SHTG, making potential marketing of zodasiran in these patients efficient for us or to be approved. We have designed a Phase 3 study of similar size to our Phase 3 PALISADE study comparing zodasiran 200 milligrams quarterly to placebo and expect to be enrolling patients this year. Assuming successful demonstration of safety and efficacy and successful regulatory submissions, zodasiran could join plozasiran in the market as early as 2028 or 2029.

針對 ANGPTL3 的單株抗體已被證明對這些患者有效，但需要每月靜脈輸注並可能導致免疫反應。我們在該族群中進行了一項探索性 2 期研究，發現了類似的益處，但每季進行一次皮下給藥更為方便。此外，這些患者通常由醫生照顧，這些醫生與治療 FCS 和 SHTG 的醫生有很大重疊，這使得 zodasiran 在這些患者中的潛在行銷對我們來說是有效的或獲得批准。我們設計了一項與我們的 3 期 PALISADE 研究規模相似的 3 期研究，對每季度服用 200 毫克 zodasiran 和安慰劑進行比較，預計今年將招募患者。假設成功證明安全性和有效性並成功提交監管申請，zodasiran 最早可能在 2028 年或 2029 年與 plozasiran 一起進入市場。

As I said at the beginning of my remarks, we hope to see plozasiran emerge as our first commercially available drug to treat FCS patients as early as this year. Based on our expected completion of enrollment in the SHTG Phase 3 study this summer, we could see SHTG Phase 3 completion in the summer of 2026 and an sNDA filing shortly thereafter.

正如我在演講開始時所說，我們希望最早在今年看到 plozasiran 成為我們第一個用於治療 FCS 患者的商業化藥物。根據我們預計今年夏天完成 SHTG 第三階段研究的招募情況，我們預計 SHTG 第三階段將於 2026 年夏天完成，並在不久之後提交 sNDA 申請。

Interestingly, also before completion of the decade, based on public guidance, progress with Phase 3 partnered programs for olpasiran in Lp(a) and fazirsiran in liver disease associated with alpha-1 antitrypsin disease could result in approvals for these programs in a similar timeframe as well as with the possibility of some of our less mature partnered programs for important orphan diseases might also find approval in that timeframe.

有趣的是，同樣在十年結束之前，根據公共指導，奧帕西蘭在 Lp(a) 治療中的應用以及法齊西蘭在 α-1 抗胰蛋白酶疾病相關肝病治療中的應用的 3 期合作計劃的進展可能會導致這些計劃在相似的時間範圍內獲得批准，而且我們一些針對重要孤兒病的不太成熟的合作計劃也可能在此時間範圍內獲得批准。

It takes patients in this business to see an important new platform rise to prominence. We feel there is some good reason to have confidence that RNA interference with joint small molecule drugs and monoclonal antibodies as a foundational technology in drug development, especially as the field, which we see Arrowhead still leading, continues to push into new cell types, opening up additional important diseases to be addressed.

只有這個行業的患者才能看到一個重要的新平台的崛起。我們認為，有充分的理由相信 RNA 幹擾與小分子藥物和單株抗體的聯合應用是藥物開發的基礎技術，特別是我們認為 Arrowhead 仍然處於領先地位的該領域，正在繼續向新的細胞類型推進，從而開闢出更多有待解決的重要疾病。

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

現在我將把電話轉給安迪戴維斯。安迪？

Thank you, Bruce. With the PDUFA date for plozasiran set for November 18, just six months away, I'm pleased to share that our commercialization efforts are advancing rapidly and with strong momentum. As discussed by Bruce, the medical affairs team is in the field helping educate the physician universe and facilitating publication of the results of Arrowhead's clinical trials.

謝謝你，布魯斯。plozasiran 的 PDUFA 日期定於 11 月 18 日，僅剩六個月的時間，我很高興地告訴大家，我們的商業化工作正在迅速推進，勢頭強勁。正如布魯斯所討論的，醫療事務團隊正在現場幫助教育醫生並促進 Arrowhead 臨床試驗結果的發布。

We're also making strong progress in building our commercial sales team. A national sales leader and a full complement of regional sales leaders are now on board and focused on hiring and onboarding top-tier talent with deep rare disease and therapeutic area expertise. Interest has been very encouraging with thousands of résumés in the queue, and we're on track to fully hire and train our sales force by late summer, ensuring ample time for target validation and disease state education in advance of launch.

我們在建立商業銷售團隊方面也取得了長足的進步。目前，一位全國銷售主管和一群區域銷售主管已加入公司，並專注於聘用和培養具有深厚罕見疾病和治療領域專業知識的頂尖人才。排隊等待的數千份履歷引起了人們極大的興趣，我們計劃在夏末之前全面招募和培訓我們的銷售人員，確保在產品推出之前有充足的時間進行目標驗證和疾病狀態教育。

Our market access team is executing effectively on our pre-approval information exchange or PIE strategy directed toward healthcare decision-makers to help them plan for our potential approval. We've now engaged with payers representing a significant number of US covered lives, delivering compelling content on the clinical value and anticipated profile of plozasiran. We're encouraged by their interest in plozasiran, especially regarding its potential to reduce triglycerides and acute pancreatitis risk.

我們的市場准入團隊正在有效地執行針對醫療保健決策者的預先批准資訊交換或 PIE 策略，以幫助他們為我們的潛在批准做好規劃。我們現在已經與代表大量美國受保生命的付款人合作，提供有關 plozasiran 的臨床價值和預期概況的引人注目的內容。他們對 plozasiran 的興趣令我們感到鼓舞，尤其是它具有降低三酸甘油酯和急性胰臟炎風險的潛力。

Additionally, our analytics team is deploying innovative technologies to identify individuals potentially living with FCS. We're connecting with these potential patients through disease state education efforts, including opportunities for them to opt in for continued communication and support.

此外，我們的分析團隊正在部署創新技術來識別可能患有 FCS 的個人。我們透過疾病狀態教育工作與這些潛在患者建立聯繫，包括讓他們選擇繼續溝通和支持的機會。

Across our research and stakeholder engagement, the clinical attributes of plozasiran continue to resonate strongly. Our market research suggests that plozasiran's deep and durable triglyceride reduction is compelling to numerous stakeholders.

在我們的研究和利害關係人的參與中，plozasiran 的臨床屬性繼續引起強烈共鳴。我們的市場調查表明，plozasiran 深度持久的降低三酸甘油酯的作用對眾多利害關係人來說具有吸引力。

The PALISADE study showed that plozasiran reduced triglycerides by approximately 80% from baseline as early as month one. With this effect sustained over 12 months and with limited variability, while placebo subjects showed variable changes ranging from plus 10% to minus 18%. As a reminder, the primary endpoint in PALISADE was the median percent change from baseline in fasting triglyceride levels at month end, where plozasiran demonstrated a placebo-adjusted change of minus 59% with the planned commercial 25-milligram dose.

PALISADE 研究表明，plozasiran 最早在第一個月就將三酸甘油酯從基線降低了約 80%。這種效果可持續 12 個月以上，且變化有限，而安慰劑組則表現出從增加 10% 到減少 18% 不等的變化。提醒一下，PALISADE 的主要終點是月末空腹三酸甘油酯水平相對於基線的中位數百分比變化，其中 plozasiran 在計劃的 25 毫克商業劑量下表現出安慰劑調整後-59% 的變化。

Our market research also suggests that healthcare providers, caregivers, and patients have a strong desire to see triglyceride levels fall below expert guideline threshold, such as 880 milligrams per deciliter and even 500 milligrams per deciliter. In PALISADE, approximately 75% of patients at the 25-milligram dose achieved levels below 880, and approximately 50% achieved levels below 500. Numerous expert guidelines emphasize the importance of maintaining triglyceride levels below 500 milligrams per deciliter as the aspirational goal to reduce acute pancreatitis risk.

我們的市場調查還表明，醫療保健提供者、護理人員和患者都強烈希望看到三酸甘油酯水平降至專家指導閾值以下，例如每分升 880 毫克，甚至每分升 500 毫克。在 PALISADE 研究中，接受 25 毫克劑量的患者中約有 75% 的藥物濃度低於 880，約有 50% 的藥物濃度低於 500。許多專家指南強調將三酸甘油酯水平維持在每分升 500 毫克以下的重要性，以此作為降低急性胰臟炎風險的理想目標。

Finally, we received feedback that patients are looking for a treatment option that minimizes disruption to their lives. Plozasiran shows a favorable dosing and safety profile. And as a reminder, plozasiran is conveniently administered once every three months, potentially minimizing treatment burden and improving adherence.

最後，我們收到回饋稱，患者正在尋找一種能夠最大限度減少對其生活影響的治療方案。Plozasiran 表現出良好的劑量和安全性。需要提醒的是，plozasiran 每三個月只需服用一次，可以最大限度地減輕治療負擔並提高依從性。

As our US launch preparations continue at full speed, we're equally pleased to report steady progress on our European commercial efforts as well. We've already established a field medical presence and are actively engaging in scientific exchange at key European scientific meetings, laying a strong foundation for a successful rollout. We remain on track and deeply motivated by the opportunity to bring investigational plozasiran to individuals living with FCS and their families in both the United States and priority countries outside the United States. We believe this potential first-in-class siRNA therapy will mark a major advancement, and we're fully committed to unlocking its patient impact.

隨著我們在美國開展的發布準備工作正在全速進行，我們同樣高興地報告我們在歐洲的商業努力也取得了穩步進展。我們已經建立了現場醫療機構，並積極參與歐洲主要科學會議的科學交流，為成功推廣奠定了堅實的基礎。我們將繼續按照計劃前進，並致力於將研究性 plozasiran 帶給美國及美國以外優先國家的 FCS 患者及其家人。我們相信這種潛在的首創 siRNA 療法將標誌著一項重大進步，我們全力致力於釋放對患者的影響。

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

現在我將電話轉給詹姆斯·漢密爾頓。

Thank you, Andy. First, I'd like to provide a status update on our two early-stage obesity programs, ARO-INHBE and ARO-ALK7.

謝謝你，安迪。首先，我想介紹一下我們的兩個早期肥胖症計畫 ARO-INHBE 和 ARO-ALK7 的最新進展。

ARO-INHBE is designed to reduce expression of activin, which is a ligand for adipose ALK7, while ARO-ALK7 is designed to reduce expression of the ALK7 receptor itself, both of which are involved in regulating adipose storage of fats. These programs have the potential to reduce visceral fat mass while simultaneously preserving lean mass, which we demonstrated in preclinical models and are now evaluating in clinical studies.

ARO-INHBE 旨在減少激活素的表達，激活素是脂肪 ALK7 的配體，而 ARO-ALK7 旨在減少 ALK7 受體本身的表達，這兩者都參與調節脂肪的脂肪儲存。這些計劃有可能減少內臟脂肪量，同時保持瘦體重，我們在臨床前模型中證明了這一點，目前正在臨床研究中進行評估。

ARO-INHBE began dosing in December of 2024 and is progressing on our planned time line. As a reminder, the Phase 1/2 study will evaluate ARO-INHBE monotherapy administered to obese otherwise healthy volunteers in both single and multiple dose escalation cohorts.

ARO-INHBE 於 2024 年 12 月開始給藥，並按照我們計劃的時間表進行。提醒一下，第 1/2 階段研究將評估對單次和多次劑量遞增隊列中的肥胖健康志願者進行的 ARO-INHBE 單一療法。

The SAD cohort dosing is now complete and the multi-dose monotherapy cohorts are actively enrolling. The study is also evaluating multiple doses of ARO-INHBE in combination with tirzepatide and these combination cohorts are actively enrolling now on our planned timeline.

SAD 隊列給藥現已完成，多劑量單藥治療隊列正在積極招募。該研究還正在評估 ARO-INHBE 與 tirzepatide 的多劑量聯合治療，這些聯合治療隊列目前正在按照我們計劃的時間表積極招募。

We anticipate the ARO-ALK7 clinical program will be up and running shortly. The design of this study is very similar to the ARO-INHBE study with SAD and MAD monotherapy cohorts and MAD cohorts in combination with tirzepatide. This study will also enroll obese otherwise healthy volunteers. Both studies are designed to assess safety, tolerability, pharmacokinetics, pharmacodynamics, and multiple exploratory obesity efficacy endpoints. We anticipate that some initial data may be available for ARO-INHBE around the end of 2025 and potentially for ARO-ALK7 shortly thereafter.

我們預計 ARO-ALK7 臨床計畫將很快啟動並運行。這項研究的設計與 ARO-INHBE 研究非常相似，其中包括 SAD 和 MAD 單一治療隊列以及 MAD 與 tirzepatide 聯合治療隊列。這項研究還將招募肥胖但健康的志願者。這兩項研究旨在評估安全性、耐受性、藥物動力學、藥效學和多項探索性肥胖療效終點。我們預計，ARO-INHBE 的一些初始數據可能在 2025 年底左右公佈，ARO-ALK7 的一些初始數據可能在不久後公佈。

Our muscle-targeted programs partnered with Sarepta, ARO-DUX4 for FSHD and ARO-DM1 for myotonic dystrophy type 1 also continue to make good progress in the Phase 1/2 studies, which are ongoing. While the decision to release data will be made jointly with Sarepta, it is our expectation that initial data release is possible in 2025.

我們與 Sarepta 合作的針對肌肉的計畫、用於治療面肩周炎 (FSHD) 的 ARO-DUX4 和用於治療 1 型強直性肌肉營養不良症的 ARO-DM1 也在正在進行的 1/2 期研究中繼續取得良好進展。雖然發布數據的決定將與 Sarepta 共同做出，但我們預計初始數據將於 2025 年發布。

Lastly, I want to highlight some top line results from Part 2 of the Phase 1/2 clinical study of ARO-C3 designed to reduce liver production of complement component 3 as a potential therapy for various complement-mediated diseases. In patients with IgA nephropathy or IgAN, ARO-C3 achieved deep and sustained reductions in alternative pathway complement activity and proteinuria. The max mean reductions in C3 was 89% with serum AH50, which is an alternative pathway hemolytic assay reduced by 85%. ARO-C3 also led to an important improvement in proteinuria with a mean reduction in spot UPCR of 41% and a maximum individual reduction of 89% from baseline up through week 24.

最後，我想強調 ARO-C3 1/2 期臨床研究第 2 部分的一些重要結果，該研究旨在減少肝臟補體成分 3 的產生，作為各種補體介導疾病的潛在治療方法。在患有 IgA 腎病或 IgAN 的患者中，ARO-C3 實現了替代途徑補體活性和蛋白尿的深度和持續降低。血清 AH50 中 C3 的最大平均減少量為 89%，這是一項減少了 85% 的替代途徑溶血試驗。ARO-C3 也使蛋白尿顯著改善，從基線到第 24 週，斑點 UPCR 平均減少 41%，個體最大減少量為 89%。

ARO-C3 was generally well tolerated and the observed duration of effect is supportive of once every three months or less frequent subcutaneous dosing. We are very pleased with these results and are planning to present fuller data set at the upcoming European Renal Association or ERA Congress in June.

ARO-C3 通常耐受性良好，觀察到的效果持續時間支持每三個月一次或更少頻率的皮下給藥。我們對這些結果非常滿意，並計劃在 6 月即將召開的歐洲腎臟協會或 ERA 大會上展示更完整的數據集。

I will now turn the call over to Ken Myszkowski.

現在我將把電話轉給 Ken Myszkowski。

Thank you, Jim, and good afternoon, everyone. As we reported today, our net income for the quarter ended March 31, 2025, was $370.4 million or $2.75 per share based on 134.5 million fully diluted weighted average shares outstanding. This compares to a net loss of $125.3 million or $1.02 per share based on 123.3 million fully diluted weighted average shares outstanding for the quarter ended March 31, 2024.

謝謝你，吉姆，大家下午好。正如我們今天所報告的，根據 1.345 億股完全稀釋加權平均流通股計算，截至 2025 年 3 月 31 日的季度，我們的淨收入為 3.704 億美元，即每股 2.75 美元。相較之下，根據截至 2024 年 3 月 31 日的季度，淨虧損為 1.253 億美元，即每股 1.02 美元（基於 1.233 億股完全稀釋加權平均流通股）。

Revenue for the quarter ended March 31, 2025, was $542.7 million. No revenue was recorded in the quarter ended March 31, 2024. Revenue in the current period relates to our license and collaboration agreement with Sarepta. As you know, the agreement with Sarepta was significant and included many assets, including clinical assets, preclinical assets and other assets to be developed. Counting guidance requires that we allocate consideration to several items, including the value of the licenses we transferred, the ongoing work of certain clinical trials that we will oversee as well as expected obligations regarding future assets to be developed.

截至 2025 年 3 月 31 日的季度營收為 5.427 億美元。截至 2024 年 3 月 31 日的季度沒有記錄任何收入。本期收入與我們與 Sarepta 的授權和合作協議有關。如您所知，與 Sarepta 的協議意義重大，包含許多資產，包括臨床資產、臨床前資產和其他有待開發的資產。計算指導要求我們將考慮因素分配給幾個項目，包括我們轉讓的許可證的價值、我們將監督的某些臨床試驗的持續工作以及有關未來資產的預期義務。

Initial fixed contract revenue to be allocated included the upfront payment of $500 million, the premium paid on the stock purchase of $84 million, and $250 million related to the five-year annual milestone payments. This totals to about $834 million, majority of which was allocated to the license agreements and recognized immediately, and the balance will be recorded as we fulfill our performance obligations.

待分配的初始固定合約收入包括 5 億美元的預付款、8,400 萬美元的股票購買溢價以及與五年年度里程碑付款相關的 2.5 億美元。總計約為 8.34 億美元，其中大部分已分配給許可協議並立即確認，餘額將在我們履行履約義務時記錄。

We recognized revenue of $542.7 million during the quarter ended March 31, 2025, and we expect the balance to be recognized over the period that we satisfy these performance obligations. These obligations include overseeing certain clinical trials as well as performing R&D work related to future clinical candidates.

我們在截至 2025 年 3 月 31 日的季度中確認了 5.427 億美元的收入，我們預計在履行這些履約義務的期間內將確認餘額。這些義務包括監督某些臨床試驗以及執行與未來臨床候選藥物相關的研發工作。

We expect $90 million to $125 million of revenue to be recognized over the next 12 months, solely related to the revenue recognition of the initial fixed contract revenue. The balance will be recognized over the next five years -- five or so years, most of which will be recognized in the first half of that time period.

我們預計未來 12 個月將確認 9,000 萬至 1.25 億美元的收入，這僅與初始固定合約收入的收入確認有關。餘額將在未來五年左右確認，其中大部分將在該時間段的前半段確認。

We also expect future revenue related to cost reimbursement for certain discovery and manufacturing activities. Future near-term milestones of $300 million related to the DM1 program are expected to be earned in the next few quarters and will be recorded in their entirety as revenue at that point as with any other future milestone payments and royalties.

我們也預期未來的收入與某些發現和製造活動的成本補償有關。與 DM1 計劃相關的 3 億美元未來近期里程碑預計將在未來幾季內實現，並將與任何其他未來里程碑付款和特許權使用費一樣，全部記錄為收入。

Total operating expenses for the quarter ended March 31, 2025, were $161.5 million compared to $126.2 million for the quarter ended March 31, 2024. Key drivers of this change were increased candidate costs as the company's pipeline of clinical candidates both increased and advanced into later stages of development.

截至 2025 年 3 月 31 日的季度總營運費用為 1.615 億美元，而截至 2024 年 3 月 31 日的季度總營運費用為 1.262 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增加和進入後期開發階段，候選藥物成本增加。

Net cash provided by operating activities during the quarter ended March 31, 2025, was $460.1 million compared with net cash used in operating activities of $92.4 million for the quarter ended March 31, 2024. Increase in cash provided by operating activities is driven by the cash received for the Sarepta agreement.

截至 2025 年 3 月 31 日的季度，經營活動提供的淨現金為 4.601 億美元，而截至 2024 年 3 月 31 日的季度，經營活動所用的淨現金為 9,240 萬美元。經營活動提供的現金增加是由於 Sarepta 協議收到的現金所致。

Turning to our balance sheet. Our cash and investments totaled $1.1 billion at March 31, 2025. Our common shares outstanding at March 31, 2025, were $138.1 million.

轉向我們的資產負債表。截至 2025 年 3 月 31 日，我們的現金和投資總額為 11 億美元。截至 2025 年 3 月 31 日，我們的流通普通股為 1.381 億美元。

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

簡要介紹完畢後，我現在將電話轉回給克里斯。

Thanks, Ken. Arrowhead is in a strong and stable position as a business, and we have made meaningful progress toward our long-term goal of developing and ultimately commercializing new innovative medicines for millions of patients. We are on schedule to launch plozasiran this year, pending regulatory approval with what we think is a best-in-class profile with meaningful differentiation from currently available therapies in FCS.

謝謝，肯。Arrowhead 作為一家企業，處於強大而穩定的狀態，我們在為數百萬患者開發並最終商業化新型創新藥物的長期目標方面取得了有意義的進展。我們計劃於今年推出 plozasiran，等待監管部門的批准，我們認為其具有同類最佳的性能，與 FCS 目前可用的療法有顯著的區別。

We are also well on our way to fully enrolling this summer our suite of Phase 3 studies designed to support regulatory submissions for the large SHTG patient population. We are funded into 2028 and potentially through multiple launches of wholly owned and partnered programs in late-stage development. In addition, we believe our technology platform is the broadest and best in the field, giving us many opportunities to receive additional capital inflows from business development in areas that are outside of our core commercial focus.

我們也正在順利地在今年夏天全面啟動我們的第三階段研究，旨在支持大量 SHTG 患者群體的監管提交。我們的資金將持續到 2028 年，並有可能透過啟動多個處於後期開發階段的全資和合作項目來實現。此外，我們相信我們的技術平台是該領域最廣泛、最好的，這為我們提供了從核心商業重點之外的領域的業務發展中獲得額外資本流入的許多機會。

Thank you for joining us today. And I would now like to open the call to your questions.

感謝您今天加入我們。現在我想開始回答你們的問題。

(Operator Instructions) Maury Raycroft, Jefferies.

（操作員指示）Maury Raycroft，Jefferies。

Congrats on the progress. And best wishes to Ken, and welcome, Dan. For INHBNE and ALK7, you've noted that the goal there is not to compete with GLP-1s, but to be used in combination. What's the latest you're seeing on how you're setting expectations for initial monotherapy and potential combo data? I guess, what you want to see in the initial update, including changes on weight loss, body composition, and relevant biomarkers?

恭喜你取得進展。向肯致以最良好的祝愿，歡迎丹。對於 INHBNE 和 ALK7，您已經注意到其目標不是與 GLP-1 競爭，而是結合使用。您對初始單一療法和潛在組合數據的預期有何最新看法？我猜，您想在初始更新中看到什麼，包括體重減輕、身體組成和相關生物標記的變化？

Thanks, Maury. So look, we're not giving any guidance on what we expect to see because this is a first-in-human study. The AML data were compelling. We saw good weight loss as a monotherapy. We saw good weight loss in combination with tirzepatide. This is -- as you know, this is a new pathway that we think could fill some of the massive amounts of white spaces in the GLP-1/GIP current standards.

謝謝，莫里。所以，我們沒有給出任何關於我們期望看到什麼的指導，因為這是一項首次人體研究。反洗錢數據令人信服。我們發現單一療法可以帶來良好的減肥效果。我們發現與 tirzepatide 結合使用可以達到良好的減肥效果。如您所知，這是一條新途徑，我們認為它可以填補 GLP-1/GIP 現行標準中的大量空白。

So look, we're looking forward to seeing what we see. Our -- the real benefits here, we think, are potentially not just weight loss, but quality of weight loss. Are we seeing the loss of visceral fat? Are we seeing a retention of lean muscle mass. We saw that in animal models.

所以，我們期待看到我們所看到的東西。我們認為，這裡的真正好處可能不僅僅是減肥，而是減肥的品質。我們是否看到了內臟脂肪的減少？我們是否看到了瘦肌肉質量的保留？我們在動物模型中看到了這一點。

We hope to see that in humans as well. And also in animals, we did not see -- this was not the result of caloric restriction. It was in the context of normal feeding. That would also be -- that sort of thing would be helpful in humans. So look, let's just see what we see.

我們希望在人類身上也能看到這一點。而且在動物身上我們也沒有看到──這不是熱量限制的結果。這是在正常餵食的情況下。這也將是──這類事情對人類是有幫助的。那麼看吧，讓我們看看我們看到了什麼。

I think we'll have our first flood of data towards the end of this year, and then it should be data-rich, gosh, virtually every quarter for the next year or so after that.

我認為我們將在今年年底獲得第一批數據，然後在接下來的一年左右的時間裡，幾乎每個季度都會有豐富的數據。

Jason Gerberry, Bank of America.

美國銀行的 Jason Gerberry。

Just ahead of the plozasiran FDA review decision, I'm wondering how you think about the robustness of your pancreatitis data and how that might look or feel a little bit differently in the package insert. I noticed Tryngolza just as a mention of the numerical incidence reduction in the clinical section.

在 FDA 對 plozasiran 做出審查決定之前，我想知道您如何看待胰臟炎數據的穩健性，以及這些數據在包裝說明書中的外觀或感覺會有何不同。我注意到 Tryngolza 只是在臨床部分提到了數值發生率的降低。

And I'm wondering if you guys feel like based on PALISADE that you might get maybe a more robust front page reference to the pancreatitis benefit? Anything you can just offer on the potential aspects of label differentiation would be much appreciated.

我想知道你們是否覺得基於 PALISADE，你們可能會得到更有力的胰臟炎益處的頭版參考？如果您能提供任何有關標籤區分潛在方面的信息，我們將非常感激。

Yes, hi. This is Bruce. We haven't had any labeling negotiations with the FDA at this point, which as you would expect, I mean we're still in the midst of the review process and label negotiations come later. So it's really impossible for me to estimate how they may view things.

是的，你好。這是布魯斯。目前我們還沒有與 FDA 進行任何標籤談判，正如您所料，我們仍處於審查過程中，標籤談判稍後再進行。因此我實在無法估計他們如何看待事物。

We obviously like our data quite a bit. We did our study differently in that we looked at patients that had confirmed pancreatitis using the Atlanta criteria, while Ionis used -- they developed a scale that also included possible and probable pancreatitis, which actually don't meet the Atlanta criteria as definite pancreatitis.

我們顯然非常喜歡我們的數據。我們的研究有所不同，我們採用亞特蘭大標準觀察已確診為胰臟炎的患者，而 Ionis 則採用 - 他們開發了一種量表，其中還包括可能和很可能的胰臟炎，但這些患者實際上並不符合亞特蘭大標準，即確診為胰臟炎。

So frankly, it's a little bit of an apples and orange comparison. And I really don't know how that might play out during labeling discussions or even in the market, but it is a little bit apples to oranges. We went, I guess, what you might say is the more conservative route, we think especially, for instance, with payers in Europe, especially that might turn out to be important. But it's -- clearly, these drugs are extremely helpful, not just in reducing triglycerides, but also in turning that reduction in triglycerides into reduced abdominal pain and pancreatitis, so we'll see.

所以坦白說，這有點像是蘋果和橘子的比較。我真的不知道這在標籤討論中甚至在市場上會如何發揮作用，但這有點像蘋果和橘子之間的比較。我想，我們走的是更保守的路線，我們認為，特別是對於歐洲的付款人來說，這可能變得特別重要。但很明顯，這些藥物非常有用，不僅可以降低三酸甘油酯，還可以將三酸甘油酯的降低轉化為減輕腹痛和胰臟炎，所以我們拭目以待。

I really can't give you any guidance for what label is going to look like. That in our business, we do the studies, we submit the FDA reviews, and the FDA decides. So ultimately, it's going to be up to them. We'll obviously discuss it with them, but I can't speak for them at all.

我真的無法給你任何關於標籤應該是什麼樣子的指導。在我們的業務中，我們進行研究，提交 FDA 審查，然後由 FDA 做出決定。所以最終，這取決於他們。我們當然會與他們討論這個問題，但我不能代表他們發言。

And let me just add here more broadly. The biology here is clear. In these patients, the higher the triglycerides, the higher the risk of pancreatitis, the higher the risk of abdominal pain. And so the goal here is to get triglycerides as low as you can. So while we are monitoring for pancreatitis, of course, and in the SHASTA-4 studies, we are looking at abdominal pain. The real thing to focus here on is how low can we get triglyceride.

讓我在這裡更廣泛地補充一下。這裡的生物學原理很清晰。在這些患者中，三酸甘油酯越高，罹患胰臟炎的風險越高，出現腹痛的風險就越高。因此，這裡的目標是盡可能降低三酸甘油酯。因此，當我們監測胰臟炎時，當然，在 SHASTA-4 研究中，我們正在觀察腹痛。這裡真正需要關注的是我們可以將三酸甘油酯降到多低。

And as I mentioned in the prepared response prepared remarks as well as we presented in the past, we get something like 75% of patients in that Phase 3 study below 880 and something like 50% below 500, and that's a real feat for these FCS patients who, as you mentioned, came into a study with a mean triglyceride level of 2,500. I think that's what we need to focus on here.

正如我在準備好的答覆和發言中提到的那樣，以及我們過去所介紹的那樣，我們發現在第三階段研究中，大約有 75％ 的患者甘油三酯水平低於 880，大約有 50％ 的患者甘油三酯水平低於 500，這對於這些 FCS 患者來說是一項真正的壯舉，正如您所提到的，正如您所提到的平均三酯。我認為這就是我們需要關注的重點。

Ellie Merle, UBS.

瑞銀的艾莉·梅爾（Ellie Merle）。

This is Jasmine on for Ellie. Thanks so much for taking the questions. So first for plozasiran in SHTG, just on acute pancreatitis, can you talk about what the latest is that you're expecting for your baseline rate of AP in your population for SHASTA-3 and 4? And what do you think the magnitude of effect that you think that you can show here is?

這是 Jasmine 為 Ellie 演唱的。非常感謝您回答這些問題。那麼首先，對於 plozasiran 在 SHTG 中的作用，僅針對急性胰臟炎，您能否談談您對您所在人群在 SHASTA-3 和 4 中 AP 基線發生率的最新預期是什麼？您認為您認為這裡可以展示的效果的程度是多少？

And then just quickly, second on zodasiran, can you clarify your current expectations in terms of potentially expanding beyond HoFH here? Thanks.

然後，關於 zodasiran 的第二點，您能否快速闡明您目前對超越 HoFH 的潛在擴張的期望？謝謝。

Let me take the second one first with zodasiran. The expansion beyond HoFH would be in potentially some sort of high-risk HeFH population. And that's actually something we discussed with the agency and proposed a narrow approach of looking only at those patients that despite maximal therapy, we were not able to get to the goal of LDL reduction that would be associated with the greatest reduction of risk.

讓我先用 zodasiran 來做第二個。HoFH 以外的擴展可能涉及某種高風險 HeFH 族群。這實際上是我們與該機構討論過的事情，並提出了一種狹義的方法，只關注那些儘管進行了最大限度的治療，但仍無法達到與最大限度降低風險相關的 LDL 降低目標的患者。

They just weren't comfortable with that because they thought -- well, I can't speak for why, but they -- maybe because they thought it was going to set precedent. But they -- to get into HeFH, they wanted a full program multiple adequate well-controlled trials about 1,500 patients or more safety, et cetera.

他們只是對此感到不舒服，因為他們認為——好吧，我不知道為什麼，但他們——也許是因為他們認為這會開創先例。但為了進入 HeFH，他們想要一個完整的計劃，多個充分、控制良好的試驗，大約 1,500 名或更多患者的安全性等等。

And it didn't make sense to us to go after such a sliver of high-risk patients with a very expensive, very long program. So we're going to stay focused on HoFH. And we do not anticipate at this time that we would expand zodasiran beyond HoFH. It's just not feasible. It's not a good use of our resources.

對我們來說，採用如此昂貴且漫長的治療計劃來治療這麼一小部分高風險患者是沒有意義的。因此我們將繼續關注 HoFH。目前，我們並不期望將 zodasiran 擴展到 HoFH 之外。這根本不可行。這對我們的資源來說不是一個好的利用方式。

Going back to plozasiran, if I understood your question of what we think the mean entry triglycerides might look like and what sort of response we might see, you would expect the chests are pretty good that we'll pretty much replicate what we saw in Phase 2.

回到 plozasiran 的問題，如果我理解了你的問題，即我們認為平均進入三酸甘油酯可能會是什麼樣子，以及我們可能會看到什麼樣的反應，你會期望胸部非常好，我們將幾乎複製我們在第 2 階段看到的情況。

And in Phase 2, the mean triglycerides in the SHTG population in that study were around 90, I think, maybe 850 to 900. And as I said, our placebo-adjusted change was 53% reduction. So substantial large reductions in triglycerides, which is why we said this trial is really -- these trials are really overpowered because even with a smaller trial in Phase 2, we have p-value 0.001.

在第 2 階段，該研究中 SHTG 族群的平均三酸甘油酯約為 90，我認為，可能是 850 到 900。正如我所說，我們的安慰劑調整變化減少了 53%。三酸甘油酯大幅減少，這就是為什麼我們說這次試驗真的——這些試驗真的具有超強的效力，因為即使是第 2 階段規模較小的試驗，我們的 p 值也為 0.001。

So it will -- it should be an impressive -- it will, but it should be an impressive -- we expect it to be an impressive reduction in triglycerides -- but the mean enrollment triglycerides around -- did I get your question right, Ellie? Did I understand your question?

所以它會 — — 它應該是令人印象深刻的 — — 它會，但它應該是令人印象深刻的 — — 我們預計甘油三酯會顯著減少 — — 但平均入學甘油三酯在 — — 我理解你的問題正確嗎，艾莉？我理解你的問題了嗎？

Yes. We also were just interested in the mean of what you expect for acute pancreatitis kind of at baseline?

是的。我們也只是想知道您對基線急性胰臟炎的預期平均值是多少？

In the pancreatitis study. Okay. Well, I would expect that's going to be closer to the FCS to the PALISADE baseline. So I would expect that the pancreatitis study baseline, it won't surprise me if it's around 2,000. It could be a little bit lower because patients, especially when they've had a history of pancreatitis, they're more susceptible to repeat pancreatitis even at lower values. But it won't shock me if it turns out to be somewhere around 2,000.

在胰臟炎研究中。好的。嗯，我希望這會更接近 FCS 和 PALISADE 基線。因此我預期胰臟炎研究基線約為 2,000，我並不會感到驚訝。該數值可能會略低一些，因為患者，尤其是有胰臟炎病史的患者，即使在較低的數值下也更容易復發胰臟炎。但如果最終數字是 2,000 左右，我不會感到震驚。

Patrick Trucchio, H.C. Wainwright & Company.

帕特里克·特魯基奧，H.C.溫賴特公司。

Congrats on all the progress. I was actually curious about your ARO-C3 and ARO-CFB programs and your latest thinking regarding the potential positioning of these compounds in complement-mediated diseases and how you're viewing these compounds? Are they core to your portfolio or there's potential here for partnering?

祝賀你取得的所有進展。我實際上對您的 ARO-C3 和 ARO-CFB 計劃以及您對這些化合物在補體介導疾病中的潛在定位的最新想法以及您如何看待這些化合物感到好奇？它們是您投資組合的核心嗎？或者它們有合作的潛力嗎？

Sure. I'll take the second part of that, and I'll -- the first part more for James. look, we are open to discussing partnerships for C3 and Factor B. Those drugs, at least in my mind, those drugs work. They do what they're designed to do. They lower C3 and the lower factor B, respectively. And we think there's a number of places they can go.

當然。我將負責第二部分，第一部分更多交給詹姆斯。看，我們願意討論 C3 和因子 B 的合作。這些藥物，至少在我看來，這些藥物是有效的。它們按照設計去做它們該做的事。它們分別降低 C3 和降低因子 B。我們認為他們可以去的地方有很多。

If we -- if push came to show, we could certainly build out a commercial presence within a fairly narrow set of opportunities. But if we can find the right partnerships, I think that would be more beneficial to us. We'll just see if we can find the right partnerships with the right economics. And right now, it's too early to tell. James, do you want to talk about some of the opportunities?

如果我們——如果努力的話，我們肯定可以在相當狹窄的機會範圍內建立商業存在。但如果我們能夠找到合適的合作夥伴，我認為這對我們來說會更有利。我們只是看看是否能夠找到具有正確經濟條件的正確夥伴關係。而現在，還言之過早。詹姆斯，你想談談一些機會嗎？

Yes, sure. So we -- the data that we talked about earlier today with ARO-C3, of course, that's the IAN data. We're still pending some data in the C3G population with that molecule. And of course, ARO-CFD is also applicable or could be used in those renal disease populations, potentially in some of the hematologic complement-mediated indications as well. And we think based on what we've seen so far with ARO-C3 that it stacks up pretty well against the other complement-mediated drugs approved or being studied in the renal indications.

是的，當然。因此，我們今天早些時候討論的 ARO-C3 數據當然是 IAN 數據。我們仍在等待該分子在 C3G 群體中的一些數據。當然，ARO-CFD 也適用於或可用於腎臟疾病族群，也可能用於某些血液補體介導的適應症。根據我們目前對 ARO-C3 的觀察，我們認為它與其他已獲批准或正在研究的用於治療腎臟疾病的補體介導藥物相比，具有相當不錯的表現。

In terms of proteinuria reduction, we talked about the 41% reduction in proteinuria with ARO-C3. I think that relative to what else is out there is pretty competitive, particularly when you look at the infrequent dose administration that can be used with RNAi dosing every three or every four months, that could have some advantages.

在減少蛋白尿方面，我們談到使用 ARO-C3 後蛋白尿減少了 41%。我認為相對於其他產品而言，它相當具有競爭力，特別是當你考慮每三或每四個月進行一次 RNAi 給藥的不頻繁劑量管理時，這可能會有一些優勢。

Andrea Newkirk, Goldman Sachs.

高盛的安德里亞紐柯克 (Andrea Newkirk)。

James, maybe one for you as you think about entering the obesity space. How are you thinking about advancing both ARO-ALK7 as well as ARO-INHBE through clinical development?

詹姆斯，當你考慮進入肥胖領域時，也許這是一個適合你的問題。您如何考慮透過臨床開發推進 ARO-ALK7 和 ARO-INHBE？

And do you have interest or capacity to advance both? Or would you look to make a decision of one versus the other following the initial datasets?

您是否有興趣或能力推進這兩項工作？或者您會根據初始資料集來做出選擇？

Sure. Yes. So our thoughts with those that from a cost standpoint, it doesn't cost us that much to do the preclinical and at least the Phase 1 development. And we have ARO-INHBE, which targets the hepatocyte expression uses the so-called GalNAc technology for delivery. That technology is pretty well vetted. We know what the safety profile at least of the platform is, and we know that we should be able to knock down the gene target in the hepatocyte.

當然。是的。因此，從成本角度來看，我們認為進行臨床前和至少第一階段的開發並不需要花費太多。我們有 ARO-INHBE，它針對肝細胞表達，使用所謂的 GalNAc 技術進行傳遞。該技術已經過嚴格審查。我們至少知道該平台的安全性，我們知道我們應該能夠敲除肝細胞中的基因標靶。

In contrast, ARO-ALK7 uses a completely different platform. The animal data look really compelling with that molecule, the platform has never been in humans before. So presumably, there's a little bit more risk there just because the platform hasn't been de-risked.

相比之下，ARO-ALK7 採用了完全不同的平台。該分子的動物數據看起來確實令人信服，該平台以前從未在人體上使用過。因此，可以推測，由於平台尚未消除風險，因此存在更多風險。

Our thought was to take both of those through Phase 1 and then get a look at the data at both the safety and the PD and efficacy data and then choose one to move forward, and there may be opportunity for partnership either with one or both of those potentially. But that was the thought of why we brought both of them into the clinic.

我們的想法是讓這兩項研究都經歷第一階段，然後查看安全性、PD 和功效數據，然後選擇一項繼續推進，並且可能有機會與其中一項或兩項建立合作關係。但這就是我們把他們倆帶到診所的原因。

And let's also be clear, these -- I do not expect these to be our last two obesity assets with our ability to address [different sites] and our ability to address potentially CNS via this blood-brain barrier platform that we've got, there are a ton of really compelling metabolic and obesity targets that I think you'll see coming down the pipe in the near term as well.

我們還要明確一點，我並不認為這些是我們最後的兩項肥胖資產，我們有能力解決[不同的部位]問題，也有能力透過我們現有的血腦屏障平台解決潛在的中樞神經系統問題，還有大量真正引人注目的代謝和肥胖目標，我想你也會在短期內看到它們出現。

Luca Issi, RBC.

盧卡·伊西（Luca Issi），RBC。

Congrats on the progress. Maybe, Bruce, circling back on a prior question, can you just maybe remind us how you're thinking about SHASTA-5 study design? What patients will be enrolled? And maybe most importantly, how many patients do you need to actually hit the stat? So if you can talk about powering assumptions, that would be much appreciated.

恭喜你取得進展。也許，布魯斯，回到先前的問題，您能否提醒我們您對 SHASTA-5 研究設計的看法？哪些患者將納入研究？也許最重要的是，你需要多少患者才能真正達到這個目標？因此，如果您能談談支持假設，我們將非常感激。

And then maybe bigger picture on plozasiran. Chris, how are you thinking about commercialization of the molecule ex US? Are you planning to do that by yourself, or you're still looking for a partner? Anything you can talk there, much appreciated.

然後也許可以對 plozasiran 有更全面的了解。克里斯，您如何看待這種分子在美國以外的商業化？您打算自己做嗎，還是仍在尋找合作夥伴？如果您能在這裡談論任何事情，我將不勝感激。

Yes, a pretty good idea of, obviously, what that is. But we also haven't said how many patients we're targeting. But again, my guess is that we may continue to all depending on sort of what the rate of pancreatitis is that we're seeing in the early days. But the trial itself is a trial enriched from the perspective that it requires that patients have had a history of pancreatitis including history of pancreatitis in the recent past, which those patients are at higher risk of pancreatitis than hyper triglyceride patients that have never had a pancreas event.

是的，顯然，這是一個很好的想法。但我們還沒有透露我們的目標患者數量。但是，我的猜測是，我們可能會繼續這樣做，這取決於早期胰臟炎的發生率。但該試驗本身是一個豐富的試驗，因為它要求患者有胰臟炎病史，包括近期有胰臟炎病史，這些患者比從未發生過胰臟事件的高三酸甘油酯患者罹患胰臟炎的風險更高。

But again, no one have done a trial like this before. So understanding exactly what the observed risk will be is something that we'll get some understanding. And of course, all be blinded, but we'll get some understanding as the trial gets underway. I think it's moving -- and that will serve you to. But it's certainly not the size of a [CVAT] or anything like that. It's much slower given the reduction of pancreatitis we saw in PALISADE, for instance. But as you know, we haven't -- we'll -- I think we'll give more detail in the future, but we're not ready to give all the all the deep detail at this point.

但之前還沒有人做過這樣的試驗。因此，我們需要準確地了解觀察到的風險是什麼。當然，這一切都是未知的，但隨著試驗的開始，我們會得到一些了解。我認為它很感人——而且會對你有幫助。但它的尺寸肯定不如 [CVAT] 或類似的東西。例如，考慮到我們在 PALISADE 看到的胰臟炎減少，這個速度要慢得多。但正如你所知，我們還沒有——我們會——我想我們將來會提供更多細節，但目前我們還沒有準備好提供所有深入的細節。

Look, so regarding your question on plozasiran. So as you know, we're full set ahead in the US for FCS and then potentially ACG open. -- rest of world, we are open to finding partners. We are preparing right now in Europe -- and can I discuss what -- how we're approaching that right now.

瞧，關於你關於 plozasiran 的問題。如您所知，我們已經在美國為 FCS 做好了充分的準備，然後也可能為 ACG 開幕做好準備。 ——世界其他地區，我們願意尋找合作夥伴。我們目前正在歐洲做準備——我可以討論一下——我們現在如何處理這個問題嗎？

Andy, do you want to discuss how we're approaching that right now?

安迪，你想討論一下我們現在如何處理這個問題嗎？

Yes, Luca. So we think the European markets, in particular, the large four European markets in the UK lend themselves extremely well to commercialization for a rare disease like FCS. Many of these patients on their patient journey or triage through a small number of centers of excellence. And so with limited infrastructure and resources, we believe we're able to help these potential FCS patients through those centers of excellence. And so as far as priority markets outside the US, those large markets in Europe and the UK and also Canada are a priority for us.

是的，盧卡。因此，我們認為歐洲市場，特別是英國的四大歐洲市場非常適合 FCS 等罕見疾病的商業化。許多患者在就診過程中都會經過少數卓越中心進行分診。因此，在基礎設施和資源有限的情況下，我們相信我們能夠透過這些卓越中心幫助這些潛在的 FCS 患者。就美國以外的優先市場而言，歐洲、英國和加拿大的大型市場是我們的優先考慮對象。

Edward Tenthoff, Piper Sandler.

愛德華·坦托夫、派珀·桑德勒。

So important to note that you guys have the review, not ever reviewed. Do you anticipate an [adcom] or anything like that? And what other steps are you taking in preparation or hopeful approval and likely launch?

值得注意的是，你們有評論，但從未評論過。您是否期待 [adcom] 或類似的東西？您還在採取哪些其他措施來準備或希望獲得批准並可能啟動？

Well, as far as the adcom goes, we've not been advised that there's an expectation for (inaudible). So at this time, we don't think that net comes in our future. As you probably know, I mean, the agency can change their opinion on that at any time if data develops in their analysis that makes them want to have an adcom for some reason. But at this point, there's no anticipation of hiccup.

嗯，就招生委員會而言，我們還沒有被告知（聽不清楚）。因此目前，我們並不認為網路會出現在我們的未來。您可能知道，我的意思是，如果分析中出現數據，導致該機構出於某種原因想要設立廣告委員會，該機構可以隨時改變他們對此的看法。但目前，還沒有預料到會出現任何問題。

So the likelihood, I suppose it's lower every day, we get closer to a potential improvement. We can't say we won't have one because they can decide at any time that they need it. But we don't see it though. And then the second part of it.

所以我認為可能性每天都在降低，我們離潛在的改善越來越近。我們不能說我們不會有這樣的機會，因為他們可以隨時決定是否需要它。但我們卻沒有看到它。然後是第二部分。

The second part was what actions are we taking to be ready for launch.

第二部分是我們採取了哪些行動來為發射做好準備。

Yeah. So I mean, I guess we talked a bit about that. From the R&D perspective, we are -- we had an educational vision under the under our medical affairs function and then the cells. So that's very much just a matter of helping physicians to be ready for a new drug coming into the SCS space was really there hasn't been any promotional effort up until the Ionis launch we've ever really for us. So there's a big --

是的。所以我的意思是，我想我們已經討論過這個問題了。從研發的角度來看，我們在醫療事務職能和細胞方面都有教育願景。因此，這在很大程度上只是為了幫助醫生為進入 SCS 領域的新藥做好準備，實際上在 Ionis 推出之前我們並沒有進行任何促銷活動。所以有一個很大的--

And Bruce, do you think the launch of Ionis is a tolling terms of sort of priming the pump a little bit there. And then hopefully, you guys coming in with a better therapy after?

布魯斯，您是否認為 Ionis 的發射對於推動太空事業發展具有一定的意義？然後希望你們能得到更好的治療？

Well, look, I think any orphan disease that has had essentially no approved therapies has always benefited from as much educational effort as you get and history tells us, and I could quote many examples where the first-approved drug really did not fully reopen that market. It often takes two or more companies to be promoting into a space, even an orphan space to really get those markets to open up and grow.

嗯，看，我認為任何基本上沒有批准療法的孤兒病總是受益於盡可能多的教育努力，歷史告訴我們，我可以舉出許多例子，第一個批准的藥物實際上並沒有完全重新開放該市場。通常需要兩家或更多公司共同進軍某個領域，甚至是孤兒領域，才能真正開拓和發展這些市場。

So it's paradoxical because people might take you better off being loan in many ways, you're actually better off when there are multiple competitors. And yes, they fitted out who gets the most share in the end. But actually, the more educational noise, the better when you're trying to open up a market like FCS and the exact same will be true for SHTG as well. more noise is better than less. And yes, the best growth usually wins the share battle, but the pie gets much bigger with more education going on.

所以這很矛盾，因為人們可能會在很多方面認為你更適合貸款，但當有多個競爭對手時，你實際上會更好。是的，他們最終決定了誰將獲得最大的份額。但實際上，當您試圖開拓像 FCS 這樣的市場時，教育噪音越多越好，對於 SHTG 來說也是如此。噪音越大越好。是的，最好的成長通常會贏得份額之戰，但隨著教育的深入，蛋糕會變得更大。

Mike Ulz, Morgan Stanley.

摩根士丹利的麥克烏爾茲。

Maybe just another one on plozasiran and the upcoming FCS launch. It sounds like you guys are making good progress in launch prep, but maybe you could just talk about or remind us the US patient population and then some of the progress you're making identifying patients and if there's any way to try and accelerate that trend?

也許只是關於 plozasiran 和即將推出的 FCS 發射的另一個。聽起來你們在啟動準備方面取得了良好的進展，但也許您可以談談或提醒我們美國的患者群體，然後談談您在識別患者方面取得的一些進展，以及是否有任何方法可以嘗試加速這一趨勢？

Yes. Thanks for the call, Mike. You'd be familiar with the epidemiological data suggesting that the prevalence of FCS in the United States would be $1 million to $13 per million. And so that spans anywhere from the hundreds of patients in the US to mid-single-digit thousands.

是的。謝謝您的來電，麥克。您可能熟悉流行病學數據，該數據表明，美國 FCS 的盛行率為每百萬 100 萬美元至 13 萬美元。因此，其範圍從美國的數百名患者到數千名患者不等。

And we think the variability around the single-digit thousands is really around whether you think about genetic STS or even clinically diagnosed FCS. That's why there's some variability there. As a reminder, of course, in PALISADE, we studied plozasiran in both genetically confirmed and clinically diagnosed patients and showed similar results. And so that's how we think about the broader market for FCS.

我們認為，個位數千分之幾的變異實際上取決於您是否考慮遺傳性 STS 或甚至是臨床診斷的 FCS。這就是為什麼存在一些變化。當然，需要提醒的是，在 PALISADE，我們對基因確診和臨床診斷的患者進行了 plozasiran 研究，並顯示了類似的結果。這就是我們對 FCS 更廣大市場的看法。

As far as patient identification, I would say that our internal team here, our analytics team and our marketing team is comprised of seasoned professionals who have cut their teeth in part of metabolic and livid specifically and are really using the latest technologies to patient fine, and ultimately to support those individuals who may have FCS and don't know that they have FCS. So patient finding will be absolutely critical as we move into the space as it is with any ultra-rare condition. And we feel like we have the people and the capabilities to excel there.

就患者識別而言，我想說，我們的內部團隊、分析團隊和行銷團隊都是由經驗豐富的專業人士組成，他們在代謝和肝硬化領域擁有豐富的經驗，並且真正使用最新技術來治療患者，並最終為那些可能患有 FCS 但不知道自己患有 FCS 的人提供支持。因此，當我們進入該領域時，找到患者是絕對至關重要的，就像任何極其罕見的情況一樣。我們覺得我們擁有人才和能力，能夠在那裡取得卓越成就。

Mayank Mamtani, B. Riley Securities.

Mayank Mamtani，B. Riley 證券。

Yes. And congrats to Ken for 16 years of service. Just maybe on the INHBE quick follow-up on the SAD data, is there anything that you are you can are willing to share what maybe the learnings there were. And on the MAD Part 1b and Part 2, which is the combination other sequential, or are they happening in parallel?

是的。恭喜肯服務了 16 年。也許只是在 INHBE 對 SAD 數據的快速跟進中，您是否願意分享從中獲得的經驗教訓。關於 MAD 第 1b 部分和第 2 部分，它們是按順序組合的，還是同時發生的？

And I'll just have follow-up for Ken, if I may.

如果可以的話，我會跟進 Ken 的情況。

Yes, sure. On the second part of the question, those -- the combo studies and the MAD noncombination studies, those are in parallel. So those are enrolling at the same time. And then I think in terms of what we can share at its as Chris said earlier, we'll have to wait and see later this year, what kind of data that we have available.

是的，當然。關於問題的第二部分，那些組合研究和 MAD 非組合研究是並行的。所以他們是同時入學的。然後我認為就我們可以分享的內容而言，正如克里斯之前所說，我們必須在今年晚些時候等待，看看我們有哪些可用的數據。

Okay. Understood. And Ken, what partnership-related milestones are factored in your -- this 2028 runway guidance? If you could maybe just clarify that and congrats again, Ken.

好的。明白了。肯，您的 2028 年發展規劃中考慮了哪些與合作相關的里程碑？如果你能澄清一下這一點並再次祝賀你，肯。

So we've included the near-term milestones that we expect to get from Sarepta. And beyond that, there are other milestones if we think they're probable of happening that we've included those as well. But we're not providing specifics on that.

因此，我們列出了我們期望從 Sarepta 獲得的近期里程碑。除此之外，如果我們認為其他里程碑有可能發生，我們也會將其納入。但我們不會提供具體細節。

Mani Faroohar, Leerink.

Mani Faroohar，Leerink。

This is Brian on for Mani. Maybe just a quick financial one. I noticed you guys started to pay down that credit facility. I'm just wondering, should we expect that to continue over the course of the year, or is this more of just a one-time pay down to kind of bring that total down?

這是 Brian，代替 Mani 上場。也許只是快速的財務問題。我注意到你們開始償還那筆信貸。我只是想知道，我們是否應該預期這種情況會在一年內持續下去，或者這只是一次性付款，以降低總額？

So the one-time pay down was because of the Sarepta agreement. There will be future payments on that, but it's only related to times when we have cash flow coming in from milestones and such. So it's only attributable to when we have some cash that's coming in.

因此，一次性付款是因為與 Sarepta 達成的協議。將來會有付款，但這僅與我們從里程碑等獲得現金流的時間有關。所以這只能歸因於我們有一些現金流入。

Brendan Smith, TD Cowen.

布倫丹·史密斯（Brendan Smith），TD Cowen。

Maybe just similar to a couple of earlier questions. I wanted to ask a little bit more on your latest thing for the CNS assets. So is the plan as of today to carry those forward internally, or are you kind of thinking that these could potentially be partnered or licensed?

可能與之前的幾個問題類似。我想進一步詢問有關 CNS 資產的最新情況。那麼，從今天起的計劃是將這些計劃在內部推進，還是您是否認為這些計劃可能會透過合作或授權的方式進行？

And then maybe more specifically for MAPT, are there any subsets of the AD population you'll look to target first? Just kind of wondering how we should think about the potential design there and segmentation of that market.

然後也許更具體地針對 MAPT，您是否會首先針對 AD 族群中的任何子集？只是想知道我們應該如何看待那裡的潛在設計和市場區隔。

Sure. James, why don't you take the and then I'll take the big question.

當然。詹姆斯，你為什麼不回答這個問題，然後我來回答這個大問題。

Sure. So the second question on MAPT. Not that at this point for the Phase 1 design. It's not entirely finalized yet but suffice to say that the main goal of the study will be to evaluate safety and measure PD markers of knockdown of how various subtypes of talent in different populations. So we've not specifically in down subtypes of AD that we plan on study.

當然。第二個問題是關於 MAPT 的。目前第一階段的設計還沒完成。雖然尚未完全定稿，但可以說，這項研究的主要目標是評估安全性並測量不同人群中各種亞型人才的 PD 標記的敲低程度。因此，我們還沒有具體研究我們計劃研究的 AD 亞型。

And regarding your first question. So as we talked about, our first three candidates in the clinic are expected to be MAPT towards the end of this year for Alzheimer's HTT, Brian, and that's already licensed to Sarepta. We expect that to be this year, too, by the end of the year and then first part of next year along for Parkinson's. So HTT is already off the docket right now. We may have ALS, (inaudible), and MAPT.

關於您的第一個問題。正如我們所說的，我們診所的前三名候選人預計將在今年年底前接受阿茲海默症 HTT 的 MAPT 治療，Brian，並且已經獲得 Sarepta 的許可。我們預計今年年底就能實現這一目標，而帕金森氏症則有望在明年年初實現這一目標。因此 HTT 現在已經不再被考慮。我們可能患有 ALS、（聽不清楚）和 MAPT。

We've always been clear two potential partners that MAPT is off limits right now. We do that as a potentially very high-value target. Look, we don't know yet if this CNS platform is going to translate from animals to humans, we will see. And so this is a bet that we're making. But we think it's a good one, given the data we've seen in the preclinical models and given the validated nature of MAPT targets. So we're holding on to that for -- at least for right now, we'll see where that goes in the future.

我們一直明確地告訴兩個潛在的合作夥伴，MAPT 目前是禁止進入的。我們將其視為一個潛在的高價值目標。瞧，我們還不知道這個 CNS 平台是否可以從動物轉換到人類，我們拭目以待。所以這是我們所做的賭注。但考慮到我們在臨床前模型中看到的數據以及 MAPT 目標的驗證性質，我們認為這是一個很好的選擇。所以我們堅持這一點——至少現在是這樣，我們將看看未來會如何發展。

Absolutely, look, we like that target a lot. And we -- if a partner comes in with -- if the right partner comes in with the right kind of deal, we would certainly consider partnering that. So that we don't feel quite as strongly at least in the near term as we do on MAPT. And then look, those are the first three we think many -- once we have this platform validated in humans, we're going to run. There's a number of additional good targets that we are developing internally.

當然，看，我們非常喜歡這個目標。如果有合適的合作夥伴加入並達成合適的交易，我們肯定會考慮與其合作。因此，至少在短期內，我們的感覺不會像在 MAPT 上那麼強烈。然後你看，這些是我們認為的前三個——一旦我們在人類身上驗證了這個平台，我們就會運行。我們正在內部開發許多其他良好目標。

And my expectation is if we see that this translates as we hope it does, you're going to see a large number of additional CNS targets, some of which we'll hold on to some of which we're partnering.

我的期望是，如果我們看到這一結果如我們所願，您將會看到大量額外的 CNS 目標，其中一些我們會堅持下去，而另一些則是我們正在合作的目標。

Prakhar Agrawal, Cantor Fitzgerald.

普拉哈·阿格拉沃爾，坎托·菲茨杰拉德。

So I know the Phase 3 SHTG readouts coming soon, if plozasiran achieved statistical significance on pancreatitis events in Phase 3, how does that impact your development strategy to have the pancreas reduction data in the label around the time of launch versus waiting for SHASTA-5 read out? And anything else you will be focusing on plozasiran SHTG trial is out?

因此，我知道第 3 階段 SHTG 讀數即將發布，如果 plozasiran 在第 3 階段對胰臟炎事件具有統計意義，那麼這會對您的開發策略產生什麼影響，即在產品上市時在標籤中提供胰臟減少數據，而不是等待 SHASTA-5 讀數？您還會關注 plozasiran SHTG 試驗的其他內容嗎？

Well, it will be interesting to see whether they can accrue enough events to actually achieve anything there, we'll see. And from our perspective, that was not a good note to -- for us to rely on that. especially in Europe to do that. Our program is also designed to look at pancreatitis events, albeit we look at definite pancreatitis, we don't look at possible cases. We just don't think that -- we think there's a high chance that's going to worry the health technology authorities in Europe. And so we really felt that we had to be -- had to definitely pancreatitis from our perspective.

好吧，看看他們是否能夠累積足夠的事件來真正取得任何成就將會很有趣，我們拭目以待。從我們的角度來看，這不是一個好兆頭——我們不應該依賴它。特別是在歐洲這樣做。我們的程序也旨在研究胰臟炎事件，儘管我們研究的是確診的胰臟炎，但我們不會研究可能的病例。我們只是不認為——我們認為這很有可能引起歐洲衛生技術當局的擔憂。因此，我們確實覺得，從我們的角度來看，我們必須－必須肯定是胰臟炎。

But we are adjudicating any pancreatitis that occurs in SHASTA-3 and SHASTA-4, and we are -- we have written those studies, and we'll see that move emerge in those two trials for the purpose specifically ties and we intend to do that. But ultimately, that for us feels like a high-risk strategy in all comers SHTG. And again, I think that a purpose-built study rather than a secondary endpoint will be much more agreeable to the payers on the most sophisticated difficult payers in the world, which mostly the European payers and some of the places as well.

但我們正在對 SHASTA-3 和 SHASTA-4 中發生的任何胰臟炎進行裁決，我們已經撰寫了這些研究報告，我們將看到這一舉措在這兩項試驗中出現，具體目的是聯繫在一起的，我們打算這樣做。但最終，對我們來說，這感覺就像是 SHTG 各方面的高風險策略。而且，我認為，專門的研究而不是次要終點的研究將更能得到世界上最複雜的困難付款人的認可，其中大部分是歐洲付款人，也包括一些地方的付款人。

David Lebowitz, Citi.

花旗銀行的 David Lebowitz。

Hi, everyone. This is Ike Lee on for David Lebowitz. We have one on pricing for plozasiran. How do you think about launching this in FCS and then waiting for the SHTG data and that in term, we expect something like Tryngolza, also getting a label expansion in SHTG and therefore, having to move from an ultra-rare pricing scheme into something that is a little bit cheaper? Is that something on your mind yet as you look towards commercialization? What are your thoughts on potentially having to navigate the ultra-rare versus much more prevalent disease pricing schemes?

大家好。這是 Ike Lee 為 David Lebowitz 主持的節目。我們有一個關於 plozasiran 定價的資訊。您如何看待在 FCS 中推出這款產品，然後等待 SHTG 數據，並且我們期待像 Tryngolza 這樣的東西，也會在 SHTG 中獲得標籤擴展，因此必須從極其罕見的定價方案轉變為稍微便宜一點的方案？當您考慮商業化時，您是否考慮過這一點？您對可能需要應對極為罕見的疾病與更為普遍的疾病的定價方案有何看法？

Sure. Look, I think we can have, and we have -- and we are in transparent building conversations with payers should we would be lucky enough to have plozasiran approved in it's a relatively narrow population. And so we would need to get reimbursed idle that is commensurate with loan within should we be lucky enough to have SHASTA-3, 4 read out well and get approved for a broader label, of course, we would bring price down conceptually. So that on a more granular level about what those two prices are, we just don't know at this point. It's going to depend on who a lot.

當然。看，我認為我們可以擁有，而且我們已經擁有了——我們正在與付款人進行透明的對話，如果我們夠幸運的話，plozasiran 能夠在相對狹窄的人群中獲得批准。因此，我們需要獲得與貸款相稱的閒置補償，如果我們夠幸運，SHASTA-3、4 能夠順利讀出並獲得更廣泛標籤的批准，當然，我們會在概念上降低價格。因此，我們目前還不清楚這兩個價格的具體細節。這很大程度上取決於誰。

So conceptually, that is our strategy, but I can't get more granular than that.

從概念上來說，這就是我們的策略，但我無法提供更詳細的說明。

Thank you. I'm showing no further questions at this time. I'd like to turn it back to Chris Anzalone for closing remarks.

謝謝。我目前沒有其他問題。我想請克里斯安札隆 (Chris Anzalone) 做最後發言。

Thanks, everyone, for joining us today. It is bittersweet to end this call. This is the last time I'm going to have Ken on my left during these calls. And as we mentioned in the prepared remarks, I really appreciate his great work for the last 16 years. And I'm going to this happen here and said that, I'm, of course, excited to have Dan on board today, to my right, maybe to my left, when Ken is gone. But thank you all for joining us today.

感謝大家今天加入我們。結束這通通話真是令人百感交集。這是我最後一次在通話過程中讓肯坐在我的左邊。正如我們在準備好的演講中提到的那樣，我非常欣賞他過去 16 年來的出色工作。我要在這裡說，當然，我很高興今天丹能加入我們，當肯離開後，他就在我的右邊，也許在我的左邊。但感謝大家今天加入我們。

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

今天的電話會議到此結束。感謝您的參與，您現在可以斷開連接了。