Arrowhead Pharmaceuticals Inc (ARWR) 2024 Q4 法說會逐字稿

Ladies and gentlemen, welcome to the Arrowhead Pharmaceuticals conference call. Throughout today's recorded presentation, all participants will be in a listen-only mode. (Operator Instructions)

女士、先生們，歡迎參加 Arrowhead Pharmaceuticals 電話會議。在今天的錄製演示中，所有參與者都將處於僅聽模式。 （操作員說明）

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

我現在將會議交給 Arrowhead 投資者關係副總裁 Vince Anzalone。請繼續，文斯。

Thank you. Good afternoon. Thank you for joining us today to discuss Arrowhead's results for its fiscal 2024 year ended, September 30, 2024. With us today from management are 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; Dr James Hamilton, Chief of Discovery and Translational Medicine, who will discuss our earlier stage development programs; and Ken Moskowsky, Chief Financial Officer, who will give a review of the financials. We will then open the call to questions.

謝謝。午安.感謝您今天加入我們，討論 Arrowhead 截至 2024 年 9 月 30 日的 2024 財年業績。 Bruce Given 博士，臨時首席醫學科學家，他將提供我們心臟代謝管道的最新資訊；安迪戴維斯 (Andy Davis)，資深副總裁兼全球心臟代謝特許經營負責人，他將提供商業化活動的最新資訊；發現和轉化醫學主管 James Hamilton 博士，他將討論我們的早期發展計劃；財務長肯·莫斯科夫斯基（Ken Moskowsky）將對財務狀況進行審查。然後我們將開始提問。

Before we begin, I would like to remind you that comments made during today's call contain certain forward-looking statements within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934. All statements other than statements of historical fact are forward-looking statements and are subject to numerous risks and uncertainties that could cause actual results to differ materially from those expressed in any forward-looking statements. For further details concerning these risks and uncertainties, please refer to our SEC filings, including our most recent annual report on Form 10-K and our quarterly reports on Form 10-Q.

在我們開始之前，我想提醒您，今天電話會議中發表的評論包含 1933 年證券法第 27A 條和 1934 年證券交易法第 21E 條含義內的某些前瞻性陳述。事實均為前瞻性陳述，並受到許多風險和不確定性的影響，可能導致實際結果與任何前瞻性陳述中表達的結果有重大差異。有關這些風險和不確定性的更多詳細信息，請參閱我們向 SEC 提交的文件，包括我們最新的 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?

我現在想將電話轉給該公司總裁兼執行長 Chris Anzalone。克里斯？

Thanks Vince. Good afternoon, everyone, and thank you for joining us today. Over the years, we built platforms capable of addressing liver, lung, adipose, CNS, skeletal muscle, cardiomyocyte, and soon, other cell types to bring RNAi therapeutics where a multitude of diseases are. Any one of these would represent an important advance in human health, but together, we believe they have a revolutionary potential.

謝謝文斯。大家下午好，感謝您今天加入我們。多年來，我們建立了能夠針對肝臟、肺臟、脂肪、中樞神經系統、骨骼肌、心肌細胞以及其他細胞類型的平台，以便為多種疾病帶來 RNAi 療法。其中任何一項都代表著人類健康的重要進步，但我們相信它們共同具有革命性的潛力。

I don't think it's hyperbole to say that we've created a machine that spits out high-quality drug candidates if you just feed it money and gene targets. Importantly, those drug candidates can be produced quickly relative to other methodologies. And given the modality and increasingly validated nature of the platforms, we have an expectation that most will do what they are designed to do.

我認為，只要給它錢和基因靶標，我們就創造了一台可以生產出高品質候選藥物的機器，這並不誇張。重要的是，相對於其他方法，這些候選藥物可以快速生產。考慮到平台的模式和日益驗證的性質，我們預計大多數平台都會做它們設計的事情。

We've always had conviction that building and constantly expanding this machine is critical to our dual mandate of serving as many patients as possible and creating long-term durable value. In the early to mid-stages of building a company around such a machine, we require partnerships to develop and commercialize non-core assets and provide capital for us to develop and commercialize our wholly owned assets while also reinvesting in the machine to expand its reach and capacity. When it's done well and in a timely fashion, it creates balance for us.

我們始終堅信，建造和不斷擴展這台機器對於我們服務盡可能多的患者和創造長期持久價值的雙重使命至關重要。在圍繞這樣的機器建立公司的早期到中期階段，我們需要合作夥伴來開發和商業化非核心資產，並為我們提供資金來開發和商業化我們的全資資產，同時也對機器進行再投資以擴大其影響範圍和容量。當它做得好並且及時時，它就會為我們創造平衡。

Of late, we have become out of balance. The partnership we announced today with Sarepta is transformational because it returns balance to our business model, helps to focus our investment thesis without constricting upside potential, and puts us on a fairly straight path to profitability. Let's take a closer look at the deal.

最近，我們已經失去了平衡。我們今天宣布與Sarepta 的合作夥伴關係具有變革性，因為它使我們的業務模式恢復平衡，有助於在不限制上行潛力的情況下集中我們的投資主題，並使我們走上一條相當直接的盈利之路。讓我們仔細看看這筆交易。

Arrowhead and Sarepta entered into a licensing and collaboration agreement that includes select programs utilizing multiple TRiM delivery systems, targeting various tissue and cell types. Under the agreement, Arrowhead will advance each program to an agreed-upon milestone and then Sarepta will assume responsibility for further development and commercialization. These include select programs from three distinct buckets: one, certain Arrowhead clinical candidates; two, certain Arrowhead non-clinical programs; and three, discovery programs to be pursued jointly between Sarepta and Arrowhead.

Arrowhead 和 Sarepta 簽署了一項許可和合作協議，其中包括利用多個 TRiM 遞送系統、針對各種組織和細胞類型的精選項目。根據協議，Arrowhead 將把每個專案推進到商定的里程碑，然後 Sarepta 將承擔進一步開發和商業化的責任。其中包括從三個不同類別中選擇的項目：一是某些 Arrowhead 臨床候選人；二、某些 Arrowhead 非臨床項目；第三，Sarepta 和 Arrowhead 共同進行的發現計畫。

In the clinical candidate bucket, Arrowhead is granting Sarepta an exclusive license to the following four programs. One, ARO-DUX4 as a potential treatment for patients with facioscapulohumeral muscular dystrophy type 1 or FSHD1. ARO-DUX4 is currently dosing patients in a Phase 1/2 clinical study. Two, ARO-DM1 as a potential treatment for patients with type 1 myotonic dystrophy or DM1. ARO-DM1 is currently dosing patients in a Phase 1/2 clinical study. Three, ARO-MMP7 as a potential treatment for idiopathic pulmonary fibrosis. ARO-MMP7 has completed dosing healthy volunteers in a Phase 1/2 clinical study and is currently dosing IPF patients to assess target engagement. And four, ARO-ATXN2 as a potential treatment for spinocerebellar ataxia 2 or SCA2.

在臨床候選項目中，Arrowhead 授予 Sarepta 以下四個項目的獨家許可。第一，ARO-DUX4 作為 1 型面肩肱型肌肉營養不良症或 FSHD1 患者的潛在治療方法。 ARO-DUX4 目前正在 1/2 期臨床研究中對患者進行給藥。第二，ARO-DM1 作為 1 型強直性肌肉營養不良或 DM1 患者的潛在治療方法。 ARO-DM1 目前正在 1/2 期臨床研究中對患者進行給藥。三、ARO-MMP7作為特發性肺纖維化的潛在治療方法。 ARO-MMP7 已在 1/2 期臨床研究中完成對健康志願者的給藥，目前正在對 IPF 患者進行給藥以評估目標參與度。第四，ARO-ATXN2 作為脊髓小腦共濟失調 2 或 SCA2 的潛在治療方法。

Arrow ataxin 2 is in a Phase 1/2 study that is currently open for enrollment. In the non-clinical bucket, Arrowhead is granting Sarepta an exclusive license to three programs that utilize Arrowhead's next generation TRiM platform for subcutaneous administration to the central nervous system. The programs are ARO-HTT for Huntington's disease, ARO-ATXN1 and ARO-ATXN3, both for spinocerebellar ataxia.

Arrow ataxin 2 正在進行 1/2 期研究，目前正在開放招募。在非臨床領域，Arrowhead 授予 Sarepta 三個項目的獨家許可，這些項目利用 Arrowhead 的下一代 TRiM 平台對中樞神經系統進行皮下給藥。這些項目包括用於治療亨丁頓舞蹈症的 ARO-HTT、用於治療脊髓小腦共濟失調的 ARO-ATXN1 和 ARO-ATXN3。

Lastly, in the discovery programs bucket, Sarepta can propose up to six new skeletal muscle cardiomyocyte or CNS targets on which Arrowhead will perform discovery and pre-clinical development. Sarepta would then receive an exclusive license to those programs and be responsible for clinical development and commercialization.

最後，在發現計畫中，Sarepta 可以提出多達 6 個新的骨骼肌心肌細胞或 CNS 目標，Arrowhead 將針對這些目標進行發現和臨床前開發。 Sarepta 隨後將獲得這些項目的獨家許可，並負責臨床開發和商業化。

During the five-year term of the agreement, Arrowhead will be excluded from working on a large list of skeletal muscle targets for its internal use or in partnership with other companies. Arrowhead will also be providing contract manufacturing services to Sarepta for clinical and eventually commercial drug supply for programs arising out of our collaboration.

在協議的五年期限內，Arrowhead 將無法參與其內部使用或與其他公司合作的大量骨骼肌目標的研究。 Arrowhead 也將向 Sarepta 提供合約製造服務，為我們合作產生的計畫提供臨床和最終的商業藥物供應。

At close of the agreement, Arrowhead would receive the following: a $500 million upfront cash payment; $325 million through the purchase by Sarepta of Arrowhead equity, priced at $27.25, representing a 35% premium to the 30-day volume weighted average price of Arrowhead stock; $250 million to be paid in annual installments of $50 million over five years; and up to $300 million in near-term payments broken up in two separate payments of $100 million and $200 million associated with the continued enrollment of certain cohorts in the Phase 1 study of ARO-DM1, which Arrowhead may achieve during the next 12 months.

協議結束時，Arrowhead 將收到以下內容： 5 億美元的預付款；透過 Sarepta 購買 Arrowhead 股權 3.25 億美元，定價為 27.25 美元，較 Arrowhead 股票 30 天成交量加權平均價溢價 35%； 2.5 億美元，五年內每年分期支付 5,000 萬美元；高達3 億美元的短期付款分為兩筆單獨付款，分別為1 億美元和2 億美元，與ARO-DM1 第一階段研究中某些隊列的繼續入組有關，Arrowhead 可能會在未來12 個月內實現此目標。

Arrowhead is eligible to receive development milestone payments between $110 million and $410 million per program and sales milestone payments between $500 million and $700 million per program. Arrowhead is also eligible to receive tiered royalties on commercial sales up to the low double digits. The total potential value of this deal exceeds $11 billion plus royalties.

Arrowhead 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。 Arrowhead 還有資格獲得高達兩位數的商業銷售分級特許權使用費。這筆交易的潛在總價值超過 110 億美元（加上特許權使用費）。

This is an important deal for both of our companies. In one transaction to give Sarepta multiple new promising pipeline opportunities all with the potential to be best in class in areas where Sarepta has extensive development, regulatory and commercial expertise, and where clear synergies exist with their existing organization.

這對我們兩家公司來說都是一筆重要的交易。在一項交易中，Sarepta 將為Sarepta 提供多個新的、有前途的管道機會，這些機會都有可能在Sarepta 擁有廣泛的開發、監管和商業專業知識以及與其現有組織存在明顯協同效應的領域成為同類最佳。

The folks at Sarepta are specialists in these areas, and we see them as having a high potential to maximize the value of the programs and be a dominant competitor. They are an ideal partner for us.

Sarepta 的人員是這些領域的專家，我們認為他們具有很大的潛力，可以最大限度地提高專案的價值並成為主導競爭對手。他們是我們理想的合作夥伴。

For Arrowhead, the deal answers two primary questions the market had about us. First, we've seen general acceptance that our technology works and that current and future drug candidates have a good chance of becoming important medicines, but there's a lack of clarity about how we would pay for them. This deal provides us with substantial capital immediately and potential access to very large amounts of additional funding throughout the life of the collaboration and beyond. This cannot be overstated. According to our long-term plan and budget, we are now funded toward the end of 2028, potentially through multiple commercial launches by Arrowhead and our partners.

對於 Arrowhead 來說，這筆交易回答了市場對我們的兩個主要問題。首先，我們看到人們普遍認為我們的技術有效，目前和未來的候選藥物很有可能成為重要的藥物，但我們如何支付這些費用尚不清楚。這筆交易為我們立即提供了大量資金，並有可能在整個合作期間及之後獲得大量額外資金。這一點怎麼強調都不為過。根據我們的長期計劃和預算，我們現在可以在 2028 年底之前獲得資金，可能透過 Arrowhead 和我們的合作夥伴的多次商業發布來實現。

Second, we built a massive clinical and pre-clinical pipeline across different therapeutic areas that has the potential to create substantial value, but A, it is difficult for the market to properly value everything there, particularly when it has been unclear what would remain wholly owned versus partnered and B, it is difficult for us to build out clinical and regulatory expertise as well as commercial infrastructure across diverse therapeutic areas. This deal goes a long way to providing a more manageable, wholly owned pipeline focused on the areas we intend to commercialize ourselves, namely in the cardiometabolic space. This more focused pipeline allows us to take advantage of the expertise we have built in clinical development and regulatory in the cardiometabolic area and our growing medical affairs and commercial presence in the space as well.

其次，我們在不同的治療領域建立了一個龐大的臨床和臨床前管道，有可能創造巨大的價值，但是，市場很難正確評估那裡的一切，特別是當尚不清楚什麼將完全保留時自有與合作相比，我們很難在不同的治療領域建立臨床和監管專業知識以及商業基礎設施。這筆交易對於提供一個更易於管理的全資管道大有幫助，該管道專注於我們打算商業化的領域，即心臟代謝領域。這個更有針對性的管道使我們能夠利用我們在心臟代謝領域的臨床開發和監管方面建立的專業知識，以及我們在該領域不斷增長的醫療事務和商業影響力。

Now, in the cardiometabolic area, we're focusing resources on the following: plozasiran, which is rapidly progressing toward commercial stage; zodasiran, which is Phase 3 ready; the APOC3-PCSK9 dimer program that we expect to file a CTA on in 2025; ARO-INHBE, which should begin enrolling a Phase 1/2 study in the next couple of months; ARO-ALK7, for which we expect to file a CTA shortly and begin enrollment by mid-2025; additional undisclosed adipose-targeted programs, undisclosed CNS programs that leverage our systemic subcutaneous delivery, and possible cardiomyocyte targeted programs. These provide us with near-, mid-, and long-term value growth and leverage common resources and expertise making us progressively more efficient for each subsequent program. This is a solid and scalable model.

現在，在心臟代謝領域，我們將資源集中在以下幾個方面： plozasiran，正在迅速進入商業化階段； zodasiran，第三階段已準備就緒；我們預計將於 2025 年提交 CTA 的 APOC3-PCSK9 二聚體計劃； ARO-INHBE，應在接下來的幾個月內開始招募 1/2 期研究； ARO-ALK7，我們預計很快就會提交 CTA 並在 2025 年中期開始註冊；其他未公開的脂肪靶向項目、利用我們的全身皮下輸送的未公開的中樞神經系統項目以及可能的心肌細胞靶向項目。這些為我們提供了近期、中期和長期的價值成長，並利用共同資源和專業知識，使我們逐步提高每個後續專案的效率。這是一個可靠且可擴展的模型。

A focused pipeline also allows us to manage the growth of our R&D expenses. Four clinical candidates and three pre-clinical programs come off our books immediately while still moving rapidly to patients who need them. On the discovery side, we believe we have an engine that is second to none and has the potential to create substantial value. So we will not slow that down.

專注的管道還使我們能夠管理研發費用的成長。四個臨床候選藥物和三個臨床前項目立即從我們的書籍中消失，同時仍在快速轉移給需要它們的患者。在發現方面，我們相信我們擁有首屈一指的引擎，並且有潛力創造巨大的價值。所以我們不會放慢速度。

We now have a partner that will take advantage of our significant discovery capacity and take as many as six new candidates that we are not yet working on into clinical studies. This is a great use of our discovery engine, represents scalable value creation, and leaves us with plenty of capacity for our own future wholly owned programs and additional partnerships.

我們現在有一個合作夥伴，將利用我們強大的發現能力，將多達六種我們尚未開發的新候選藥物納入臨床研究。這是對我們的發現引擎的一個很好的利用，代表了可擴展的價值創造，並為我們自己未來的全資項目和其他合作夥伴關係留下了充足的能力。

Another important piece of the Sarepta partnership that may be overlooked is the manufacturing component. Providing clinical and commercial material to Sarepta for programs included in this deal soaks up current excess manufacturing capacity in our new Verona manufacturing plant and defrays our operating costs. It also provides Sarepta with a high-quality, cost-effective partner for important R&I medicines that will develop and ultimately commercialize.

Sarepta 合作夥伴關係中另一個可能被忽視的重要部分是製造部分。向 Sarepta 提供本次交易中包含的項目的臨床和商業材料，可以吸收我們新的維羅納製造工廠當前過剩的製造能力，並支付我們的營運成本。它還為 Sarepta 提供了一個高品質、具有成本效益的合作夥伴，用於開發並最終商業化的重要 R&I 藥物。

Our cardiometabolic focus and the Sarepta license agreement together do not capture all of our promising programs. Rather, we believe there are additional programs we have that could be partnered at some point to capture additional value and ensure that they reach the patients who need them. The programs that sit in this category are the following: ARO-RAGE for asthma and COPD, which is Phase 2 ready, and we are assessing various options and designs for moving forward; ARO-PNPLA3 for MASH, which is also Phase 2 ready and for which we are also considering options; ARO-C3 and ARO-CFB in the complement space, which should both have clinical readouts by mid-2025; ARO-MAPT for Alzheimer’s and other tauopathies as well as ARO-SCNA for Parkinson's which both use what we believe is our very promising subcutaneous TRiM system for CNS delivery and are on schedule for CTAs in 2025.

我們對心臟代謝的關注和 Sarepta 許可協議並沒有涵蓋我們所有有前景的項目。相反，我們相信我們還有其他項目可以在某個時候進行合作，以獲取額外價值並確保它們到達需要它們的患者手中。屬於這一類別的項目如下： ARO-RAGE 用於氣喘和慢性阻塞性肺病，已準備好進入第二階段，我們正在評估各種方案和設計以推動進展；用於 MASH 的 ARO-PNPLA3，它也已做好第 2 階段的準備，我們也在考慮其選項；補體領域的 ARO-C3 和 ARO-CFB，到 2025 年中期都應該有臨床讀數；用於治療阿茲海默症和其他tau蛋白疾病的ARO-MAPT 以及用於治療帕金森氏症的ARO-SCNA 均使用我們認為非常有前途的皮下TRiM 系統進行中樞神經系統輸送，並按計劃於2025年進行CTA。

We're excited about each of these programs, and while we do not require partners immediately, our current strategy is to eventually find the right companies to develop and commercialize each one. In the meantime, we are assessing timing and possible additional development that could maximize risk-adjusted value to us.

我們對這些專案中的每一個都感到興奮，雖然我們並不立即需要合作夥伴，但我們目前的策略是最終找到合適的公司來開發和商業化每個專案。同時，我們正在評估時機和可能的額外開發，以最大限度地提高我們的風險調整價值。

As part of this pipeline focus, we have decided not to pursue further development of ARO-MUC5AC. To be clear, this decision was not due to any emerging safety issue but rather the inability to reliably assess target engagement with the availability of biomarkers. While we still believe that ARO-MUC5AC is an intriguing target for muco-obstructive diseases, we believe that we have programs without this biomarker limitation where we can better allocate capital.

作為該系列重點的一部分，我們決定不再進一步開發 ARO-MUC5AC。需要明確的是，這項決定並不是由於任何新出現的安全問題，而是由於無法可靠地評估目標與生物標記可用性的接觸程度。雖然我們仍然相信 ARO-MUC5AC 是黏膜阻塞性疾病的一個有趣的靶標，但我們相信我們的計畫沒有這種生物標記的限制，我們可以更好地分配資本。

We have also made great progress with our lead program and potential first commercial product, plozasiran, from a clinical, regulatory, and commercial perspective, which Bruce and Andy will discuss in a moment. We now feel like all the pieces are in place to accelerate growth.

從臨床、監管和商業角度來看，我們的主導項目和潛在的第一個商業產品 plozasiran 也取得了巨大進展，Bruce 和 Andy 稍後將對此進行討論。我們現在感覺所有的準備工作都已到位，可以加速成長。

Let's review what we see as the key steps that enable that growth. We have generated important Phase 3 data in the PALISADE study of plozasiran in patients with genetically defined and clinically diagnosed FCS, forming the basis of submission of our first NDA. This is a big step for any biotech company, and we were excited to make that submission earlier this month. We now have field and home office, medical affairs organizations in place within clinical development.

讓我們回顧一下我們認為實現這一成長的關鍵步驟。我們在 plozasiran 在基因定義和臨床診斷的 FCS 患者中進行的 PALISADE 研究中產生了重要的 3 期數據，構成了我們提交第一份 NDA 的基礎。對於任何生物技術公司來說，這都是一大進步，我們很高興在本月初提交了該意見。我們現在在臨床開發領域設有現場和家庭辦公室、醫療事務組織。

We have also built out the key headquarters, commercial infrastructure and are in the process of building out a commercial field team, right-sized for this rare disease. We are confident that we will be ready for our potential first commercial launch in 2025, provided we receive positive FDA review and approval. We have also begun leveraging outsourced resources for a European commercial launch provided we receive positive positive EMA review and approval which we intend to seek in 2025.

我們也建立了重要的總部和商業基礎設施，並正在建立一個規模適合這種罕見疾病的商業現場團隊。我們相信，只要獲得 FDA 的積極審查和批准，我們就能為 2025 年首次商業推出做好準備。我們也開始利用外包資源在歐洲進行商業發布，前提是我們獲得了 EMA 的積極審查和批准，我們打算在 2025 年尋求這項批准。

We also have comprehensive plozasiran Phase 3 program for the large patient population with severe hypertriglyceridemia or SHTG. We believe there are 3 million to 4 million people in the US making up this population, and there are very limited options -- treatment options at present. We expect the studies needed for regulatory approval to be fully enrolled by mid-year 2025, leading to final patient visits in the middle of 2026 and potential sNDA fine at the end of 2026 or early 2027.

我們也針對患有嚴重高三酸甘油脂血症或 SHTG 的大量患者群體制定了全面的 plozasiran 3 期計劃。我們相信美國有 300 萬到 400 萬人構成了這一人群，而目前的治療選擇非常有限。我們預計監管部門批准所需的研究將在 2025 年中期完成全部入組，最終患者將在 2026 年中期就診，並可能在 2026 年底或 2027 年初獲得 sNDA 罰款。

We see this as a large patient population with inadequate treatment options that alone could make plozasiran a $2 billion to $3 billion per year drug. Further, we continue to see a big opportunity in a larger mixed hyperlipidemia markets. Plozasiran has always looked like potentially powerful medicine for secondary prevention of ASCVD as well as primary prevention for high-risk patients by the KOL community we've been working with. Addressing this patient population approximately doubles our revenue forecast for plozasiran but would require a cardiovascular outcomes trial or CVOT for approval. As such, we are waiting until we have better visibility on additional capital before launching this trial.

我們認為，大量患者群體的治療選擇不足，僅靠這一點就可以使 plozasiran 成為每年價值 20 億至 30 億美元的藥物。此外，我們繼續在更大的混合高血脂市場中看到巨大的機會。 Plozasiran 一直被我們一直合作的 KOL 社群視為 ASCVD 二級預防以及高風險病患一級預防的潛在強效藥物。解決這群患者的問題大約使我們對 plozasiran 的收入預測增加一倍，但需要心血管結果試驗或 CVOT 才能獲得批准。因此，我們正在等待，直到我們對額外資本有了更好的了解，然後再啟動此試驗。

Arrowhead now has a combination of traits that puts it in the strongest position ever in the history of the company. These include substantial immediate capital, the expectation of large amounts of additional non-dilutive capital in coming years via existing partnerships, a lead program that is gearing up for commercial launch, a lead program that could see substantial label expansion in coming years, a focused cardiometabolic pipeline that spans early discovery to Phase 3 ready, a discovery engine capable of creating new candidates rapidly, strong partners in place for non-core assets, several non-core programs that could be partnered in the future for additional non-dilutive, near- and long-term capital and a state-of-the-art, high-capacity manufacturing facility that is qualified for clinical material now and could be qualified for commercial material soon.

Arrowhead 現在擁有的一系列特徵使其處於公司歷史上最強大的地位。其中包括大量的直接資本、未來幾年透過現有合作夥伴關係獲得大量額外非稀釋資本的預期、一個正在為商業啟動做準備的主導計劃、一個可能在未來幾年看到標籤大幅擴張的主導計劃、一個重點關注的計劃。額外的非稀釋性、近期的- 長期資本和最先進的高產能製造設施，目前已具備臨床材料資格，並且很快就能獲得商業材料資格。

With that overview, I would now like to turn the call over to Dr. Bruce Given, who will discuss what we've accomplished with plozasiran and the status of the Phase 3 program. Bruce?

有了上述概述，我現在想將電話轉給 Bruce Given 博士，他將討論我們在 plozasiran 方面所取得的成就以及第 3 階段專案的狀態。布魯斯？

Thank you, Chris, and good afternoon, everyone. It has been a remarkable year for plozasiran. We've had a series of high-impact presentations at major international academic meetings accompanied by four simultaneous publications and highly selective, high-impact medical journals. We also initiated our Phase [2] program in severe hypertriglyceridemia, or SHTG, this summer and culminating with our New Drug Application or NDA submission to the US FDA earlier this month. I'll review some of those highlights over the next few minutes.

謝謝克里斯，大家下午好。對於 plozasiran 來說，這是非凡的一年。我們在主要國際學術會議上進行了一系列高影響力的演講，並同時出版了四份出版物和高選擇性、高影響力的醫學期刊。今年夏天，我們也啟動了針對嚴重高三酸甘油脂血症（SHTG）的第 [2] 期計劃，並於本月初向美國 FDA 提交了新藥申請或新藥申請（NDA）。我將在接下來的幾分鐘內回顧其中的一些亮點。

First, it was a great pleasure to submit our NDA for plozasiran and in the orphan condition of familial chylomicronemia syndrome or FCS to the FDA. That started the clock for their validation process, which is expected to take up to 60 days. If the FDA determines that the filing is complete and accepted for review, they will inform us at that time of the PDUFA date by which a decision on approval may be made. Because the FDA has granted plozasiran breakthrough therapy designation, we are hopeful for a priority review, but that determination will be made solely at the discretion of the FDA.

首先，我們非常高興向 FDA 提交 plozasiran 和家族性乳糜微粒血症綜合症或 FCS 孤兒藥物的 NDA。他們的驗證過程就此開始，預計最多需要 60 天。如果 FDA 確定備案已完成並接受審查，他們將在屆時通知我們 PDUFA 日期，以便做出批准決定。由於 FDA 已授予 plozasiran 突破性療法認定，我們希望獲得優先審查，但這項決定將完全由 FDA 自行決定。

Our database for the pivotal PALISADE study in subjects with genetically confirmed or clinically diagnosed FCS was only locked on May 16 of this year. So this was an excellent performance by the Arrowhead team, especially given that this was the organization's first NDA. We look forward to hearing the FDA's filing decision.

我們針對基因確診或臨床診斷 FCS 受試者的關鍵 PALISADE 研究資料庫於今年 5 月 16 日才鎖定。因此，Arrowhead 團隊的表現非常出色，特別是考慮到這是該組織的第一份保密協議。我們期待聽到 FDA 的備案決定。

If we take a step back to assess the results that have been generated with plozasiran over the last year at medical meetings and in publications, a clear picture emerges. As data from the Phase 2 trials were presented and published in JAMA Cardiology and the New England Journal of Medicine in the first half of the year. We saw in the MUIR study of patients with mild to moderate hypertriglyceridemia in the context of mixed hyperlipidemia and in patients with severe hypertriglyceridemia in SHASTA-2 that plozasiran produced deep and durable reductions in apolipoprotein C-III or APOC3 with quarterly subcutaneous dosing, and that these reductions led to deep and durable reductions in triglycerides, remnant cholesterol, apolipoprotein B or ApoB, and non-HDL cholesterol, while substantially increasing HDL cholesterol as we had anticipated based on human genetic data and our Phase I study results.

如果我們退後一步來評估去年在醫學會議和出版物中使用 plozasiran 產生的結果，就會出現清晰的情況。今年上半年，二期試驗的數據已在《美國醫學會雜誌心臟病學》和《新英格蘭醫學雜誌》發表。我們在對混合性高脂血症背景下的輕度至中度高三酸甘油酯血症患者和SHASTA-2 中的重度高三酸甘油酯血症患者進行的MUIR 研究中看到，每季度皮下給藥物plozasiran 可以深度且持久地降低載脂蛋白C-III 或APOC3，並且這些減少導致三酸甘油酯、殘餘膽固醇、載脂蛋白B 或ApoB 和非HDL 膽固醇深度持久減少，同時大幅增加HDL 膽固醇，正如我們根據人類遺傳數據和第一階段研究結果所預期的。

While Phase 2 data require replication and expansion in Phase 3 studies, which I'll describe in a moment, we learned a number of important things from these results. First, we evaluated doses from 10 to 50 milligrams and determined in both of these studies that we could confidently select 25 milligrams as being at the top of the dose response curve for efficacy while also having safety and tolerability that appeared favorable. On this basis, we chose the 25-milligram dose, administered every three months to (technical difficulty) Phase 3 development in both mixed hyperlipidemia and severe hypertriglyceridemia.

雖然第二階段的數據需要在第三階段的研究中複製和擴展（我稍後將對此進行描述），但我們從這些結果中學到了許多重要的東西。首先，我們評估了 10 至 50 毫克的劑量，並在這兩項研究中確定，我們可以自信地選擇 25 毫克作為療效劑量反應曲線的頂部，同時還具有似乎有利的安全性和耐受性。在此基礎上，我們選擇了25毫克劑量，每三個月給藥一次，以進行混合性高血脂症和嚴重高三酸甘油脂血症的（技術難度）3期開發。

Second, the reductions in our lipid targets were substantial and consistent with the human genetic data from individuals who had inherited genetic variants with low or no activity for APOC3 who displayed favorable lipid profiles and appear to have reduced risk for cardiovascular disease. Finally, these individuals inheriting loss of function APOC3 genes have been thought to have no negative safety or tolerability issues, and our Phase 2 data suggests that this therapy may well be well tolerated in Phase 3 studies.

其次，我們的血脂目標的降低是顯著的，並且與遺傳了APOC3 活性低或無活性的遺傳變異的個體的人類遺傳數據一致，這些個體表現出良好的血脂特徵，並且似乎降低了心血管疾病的風險。最後，這些遺傳了 APOC3 基因功能喪失的個體被認為沒有負面的安全性或耐受性問題，我們的 2 期數據表明，這種療法在 3 期研究中可能具有良好的耐受性。

In fact, subjects from the Phase 2 MUIR and SHASTA-2 studies were offered the opportunity to enter a long-term extension study called ARO-APOC3 2003, which was reported out at the American Heart Association Scientific Sessions on November 18. Those data in 418 patients suggested that lipid changes remained essentially unchanged, out 15 to 18 months while receiving plozasiran 25 milligrams quarterly with no new safety signals detected. Hemoglobin A1c was essentially unchanged over that period.

事實上，第 2 階段 MUIR 和 SHASTA-2 研究的受試者有機會參加一項名為 ARO-APOC3 2003 的長期擴展研究，該研究於 11 月 18 日在美國心臟協會科學會議上報告。患者表示，在每季接受25 毫克plozasiran 治療的15 至18 個月內，血脂變化基本上保持不變，沒有檢測到新的安全訊號。在此期間，糖化血紅蛋白基本上沒有變化。

Most of you will be familiar with our Phase 3 PALISADE study that reported at the European Society of Cardiology with another simultaneous publication in the New England Journal Medicine. We observed an 80% reduction from baseline in median triglycerides at month 10 with the 25-milligram dose, while placebo subjects showed a reduction of 17%. The reduction in triglycerides in month 10 was highly statistically significant with a p-value less than 0.0001.

你們中的大多數人都會熟悉我們的 3 期 PALISADE 研究，該研究在歐洲心臟病學會上進行了報道，同時在《新英格蘭醫學雜誌》上發表了另一篇文章。我們觀察到 25 毫克劑量的受試者在第 10 個月時三酸甘油酯中位數較基線降低了 80%，而安慰劑受試者則降低了 17%。第 10 個月三酸甘油酯的降低具有高度統計顯著性，p 值小於 0.0001。

This study also included a 50-milligram quarterly dose group with plozasiran with similar significant results, which together with the results from MUIR and SHASTA-2 have convinced us that we have achieved the maximum efficacy possible for the APOC3 mechanism with the 25-milligram dose, regardless of indication. Because both 25 and 50 milligrams achieved significant reductions on the primary triglyceride endpoint, we were allowed to assess the significance of our alpha-controlled secondary endpoints. In this regard, APOC3 reductions at 10 and 12 months and average triglyceride reductions at 10 and 12 months combined were also highly significant.

這項研究還包括 plozasiran 的 50 毫克季度劑量組，具有類似的顯著結果，與 MUIR 和 SHASTA-2 的結果一起使我們相信，我們已經用 25 毫克劑量實現了 APOC3 機制的最大功效，無論指示如何。由於 25 毫克和 50 毫克均實現了主要三酸甘油酯終點的顯著降低，因此我們可以評估 α 控制的次要終點的重要性。在這方面，APOC3 在 10 個月和 12 個月時的降低以及平均三酸甘油酯在 10 個月和 12 個月時的降低也非常顯著。

Our final alpha-controlled secondary was a comparison of incidents of expert-adjudicated cases of acute pancreatitis for the placebo group compared to a combined group of the 25 and 50 milligrams plozasiran dose cohorts. This important endpoint showed a statistically significant 83% reduction in incidence of acute pancreatitis with plozasiran with a p-value of 0.029.

我們最終的 α 對照第二項研究是對安慰劑組經專家判定的急性胰臟炎病例與 25 毫克和 50 毫克 plozasiran 劑量組的合併組進行比較。這項重要終點顯示，使用 plozasiran 後，急性胰臟炎的發生率顯著降低 83%，p 值為 0.029。

Not surprisingly, given the reduction in pancreatitis, high percentages of patients reached recognized risk reduction thresholds for triglycerides with a clinical dose of 25 milligrams quarterly. In fact, 75% of patients reached levels below 880 milligrams per deciliter, and 50% were able to reach triglyceride levels less than 500 milligrams per deciliter.

毫不奇怪，考慮到胰臟炎的減少，高比例的患者達到了公認的三酸甘油酯風險降低閾值，每季臨床劑量為 25 毫克。事實上，75% 的患者三酸甘油酯水平低於 880 毫克/分升，50% 的患者三酸甘油酯水平低於 500 毫克/分升。

There were a number of exploratory endpoints in the study, which we reported at AHA and simultaneously published in the high-impact AHA Journal, Circulation. Meaningful reductions in remnant cholesterol and non-HDL cholesterol were shown as well as increases in HDL cholesterol. The expected increases in mean LDL cholesterol were seen but remained below guideline levels for cardiovascular risk reduction. Finally, longitudinal data was shown from month 1 through 12 for the clinical 25-milligram dose indicating that the reductions in triglycerides from baseline of approximately 80% were similar whether patients had genetically confirmed or clinically diagnosed FCS, a finding that we believe is important.

研究中有許多探索性終點，我們在 AHA 上進行了報告，並同時發表在高影響力的 AHA 期刊《Circulation》上。殘餘膽固醇和非高密度脂蛋白膽固醇顯著減少，高密度脂蛋白膽固醇增加。平均低密度脂蛋白膽固醇出現了預期的增加，但仍低於降低心血管風險的指導水準。最後，臨床25 毫克劑量從第1 個月到第12 個月的縱向數據表明，無論患者是否患有基因證實或臨床診斷的FCS，三酸甘油酯較基線降低約80% 的情況相似，我們認為這一發現很重要。

Tolerability has been good across all three study populations. The most common treatment-emergent adverse events for the PALISADE FCS study were abdominal pain, COVID-19, nasopharyngitis, and nausea. For the Phase 2 MUIR and SHASTA-II studies, the most frequent adverse events were COVID-19, upper respiratory tract infection, headache, type 2 diabetes mellitus, and abdominal pain.

所有三個研究族群的耐受性均良好。 PALISADE FCS 研究中最常見的治療相關不良事件是腹痛、COVID-19、鼻咽炎和噁心。對於 2 期 MUIR 和 SHASTA-II 研究，最常見的不良事件是 COVID-19、上呼吸道感染、頭痛、2 型糖尿病和腹痛。

While all of this was going on, we were also busy obtaining regulatory input and initiating our Phase 3 program for plozasiran in SHTG. Our twin pivotal Phase 3 studies in patients with SHTG called SHASTA-3 and SHASTA-4 were initiated in the middle of the year. We now have centers open in the US, Europe, and China with new centers opening weekly, and we have patient screening and enrollment ongoing in all three territories.

在進行這一切的同時，我們也忙於獲取監管意見並啟動 SHTG 中 plozasiran 的第三階段計劃。我們針對 SHTG 患者進行的兩項關鍵 3 期研究（稱為 SHASTA-3 和 SHASTA-4）於今年年中啟動。我們現在在美國、歐洲和中國開設了中心，每週都會開設新中心，並且我們在這三個地區正在進行患者篩檢和登記。

We are also conducting a Phase 3 study in patients with mixed hyperlipidemia named MUIR-3, which is there to provide safety numbers needed for the expected SHTG supplement to our plozasiran NDA. All three of these studies are largely patterned after their Phase 2 counterparts, except that patients will receive four quarterly doses of 25 milligrams or placebo for a full year of treatment and follow-up before entering into an extension if they so choose.

我們也在混合性高脂血症患者中進行一項名為 MUIR-3 的 3 期研究，該研究旨在為我們的 plozasiran NDA 提供預期的 SHTG 補充所需的安全數據。這三項研究在很大程度上都是仿照2 期研究的模式進行的，只是患者將接受每季度4 劑25 毫克的劑量或安慰劑，進行一整年的治療和隨訪，然後如果他們願意的話，可以進行延期。

We are also getting ready to start SHASTA-5, a first-of-its-kind study, where the primary outcome will be reduction in acute pancreatitis in patients with SHTG and a history of pancreatitis. This study has not been requested by regulatory authorities and is not considered to be on the critical path for the SHTG submissions. Rather, this is a study that we are conducting for payers and to support the market.

我們也準備好啟動 SHASTA-5，這是一項同類研究，其主要結果是減少 SHTG 和有胰臟炎病史的患者的急性胰臟炎發生率。這項研究尚未得到監管機構的要求，也不被認為是 SHTG 提交的關鍵路徑。相反，這是我們為付款人進行的一項研究，旨在支持市場。

Finally, regarding CAPITAN, our planned outcome study with plozasiran for prevention of cardiovascular events in patients with elevated triglycerides and a history of atherosclerotic cardiovascular disease, or ASCVD, or at high risk for ASCVD. We continue to receive feedback from global regulatory authorities in our Executive Committee and expect to have our final dose -- I'm sorry -- our final protocol design in the first half of 2025. So in summary, an amazing 2024 for plozasiran is setting up a busy and exciting 2025.

最後，關於 CAPITAN，我們計劃對 plozasiran 進行結局研究，用於預防三酸甘油酯升高、有動脈粥狀硬化性心血管疾病 (ASCVD) 病史或 ASCVD 高風險患者的心血管事件。我們繼續收到執行委員會中全球監管機構的回饋，並期望在2025 年上半年完成我們的最終劑量——抱歉——我們的最終方案設計。到來迎接忙碌而激動人心的 2025 年。

I will now turn the call over to Andy Davis. Andy?

我現在將把電話轉給安迪戴維斯。安迪？

Thank you, Bruce. Just over one week ago, our team was at the American Heart Association Scientific Sessions 2024, or AHA, where we announced new results from the Phase 3 PALISADE study and the open-label extension from the Phase 2 MUIR and SHASTA-2 studies of investigational plozasiran. And the feedback we collected on site from both physicians and patient societies continues to be very encouraging. We hear lots of enthusiasm about the differentiating attributes of plozasiran, which generally fall into five value pillars that you've heard me speak about before.

謝謝你，布魯斯。就在一週前，我們的團隊參加了 2024 年美國心臟協會科學會議 (AHA)，會上我們宣布了 3 期 PALISADE 研究的新結果以及 2 期 MUIR 和 SHASTA-2 研究的開放標籤擴展普洛扎西蘭。我們從醫生和患者協會現場收集的回饋仍然非常令人鼓舞。我們聽到很多人對 plozasiran 的差異化屬性充滿熱情，這些屬性通常分為五個價值支柱，您之前聽過我談過。

First, the reduction in triglycerides has been both deep and durable. In PALISADE, as Bruce mentioned, plozasiran reduced triglycerides by around 80% from baseline as early as month one and maintain this reduction with limited variation throughout the full 12-month treatment period.

首先，三酸甘油酯的降低既深入又持久。正如 Bruce 所提到的，在 PALISADE 中，plozasiran 早在第一個月就使三酸甘油酯較基線降低了約 80%，並在整個 12 個月的治療期間保持這種降低，變化有限。

Second, and for really the first time, patients and their doctors see real hope of achieving triglyceride levels below guideline-directed risk thresholds associated with acute pancreatitis, such as 880 and even 500 milligrams per deciliter. Around half of the patients at the 25-milligram dose in PALISADE maintain TGs below 500 milligrams per deciliter, with approximately 75% achieving levels below 880 milligrams per deciliter.

其次，患者和他們的醫生第一次真正看到了三酸甘油酯水平低於指南規定的與急性胰臟炎相關的風險閾值（例如每分升 880 甚至 500 毫克）的真正希望。在接受 25 毫克劑量的 PALISADE 治療的患者中，大約一半的患者將 TG 維持在 500 毫克/分升以下，其中約 75% 的患者達到了低於 880 毫克/分升的水平。

To support physician education on guideline-directed risk thresholds, we announced on FCS Awareness Day earlier this month, the launch of a new disease awareness campaign called We'll Get There Soon. A key focus of our messaging is to educate the physician community about expert guidelines from several professional medical societies, 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進行教育，我們在本月早些時候的 FCS 意識日宣布啟動一項名為「我們很快就會到達那裡」的新疾病意識活動。我們傳遞訊息的一個重點是向醫生群體提供來自多個專業醫學協會的專家指南的教育，這些指南建議將三酸甘油酯水平保持在 500 毫克/分升以下，以降低急性胰臟炎的風險。

Third, the triglyceride reductions in PALISADE were generally consistent in patients with genetically confirmed and clinically diagnosed FCS. As I mentioned at the outset, new results from PALISADE were presented in an oral presentation at AHA and simultaneously published in the journal, Circulation. Plozasiran at the 25-milligram dose induced rapid, deep, and sustained reductions in APOC3 of greater than minus 90% and in triglycerides of approximately minus 80%, independent of gene variants causing FCS. As Bruce mentioned, we believe this supports the potential value of plozasiran in patients with clinically diagnosed disease regardless of genetic status.

第三，PALISADE 中三酸甘油酯的降低在基因確診和臨床診斷的 FCS 患者中基本一致。正如我在開頭提到的，PALISADE 的新結果在 AHA 的口頭報告中進行了介紹，並同時發表在《Circulation》雜誌上。 25 毫克劑量的 Plozasiran 誘導 APOC3 快速、深度和持續減少超過 -90%，三酸甘油酯減少約 -80%，與引起 FCS 的基因變異無關。正如 Bruce 所提到的，我們相信這支持了 plozasiran 對於臨床診斷疾病的患者的潛在價值，無論遺傳狀況如何。

Fourth, plozasiran is the first and only investigational medicine to report a statistically significant reduction in the risk of developing acute pancreatitis in patients with genetically confirmed and clinically diagnosed FCS. This important endpoint showed a statistically significant 83% reduction in the incidence of acute pancreatitis with plozasiran. This is the outcome of most importance for physicians, patients, and payers.

第四，plozasiran 是第一個也是唯一一個報告在基因證實和臨床診斷的 FCS 患者中顯著降低急性胰臟炎風險的研究藥物。這一重要終點顯示，使用 plozasiran 後，急性胰臟炎的發生率顯著降低了 83%。對於醫生、病人和付款人來說，這是最重要的結果。

And lastly, number five, plozasiran demonstrated favorable safety and tolerability, largely similar to placebo and is conveniently dosed every three months, reducing the treatment burden on both physicians and patients with only four injections per year. To support this value proposition, we've built best-in-class medical market access and marketing organizations, and our teams are solidly in place.

最後，第五，plozasiran 表現出良好的安全性和耐受性，與安慰劑基本相似，每三個月給藥一次，方便，每年只需注射四次即可減輕醫生和患者的治療負擔。為了支持這一價值主張，我們建立了一流的醫療市場准入和行銷組織，我們的團隊已經穩固到位。

As Chris mentioned, the medical affairs group is fielding medical science liaisons to conduct scientific exchange. And on the sales and marketing side, we've recently hired our National Sales Director, who will be executing our field force hiring plans over the next several months. We are on track, and we're incredibly excited about 2025 and the possibility of bringing investigational plozasiran to those FCS patients and their families who are burdened by this condition.

正如克里斯所提到的，醫學事務小組正在派遣醫學科學聯絡員來進行科學交流。在銷售和行銷方面，我們最近聘請了全國銷售總監，他將在接下來的幾個月內執行我們的現場人員招募計畫。我們正在步入正軌，我們對 2025 年感到非常興奮，並且有可能將研究性 plozasiran 帶給那些患有這種疾病的 FCS 患者及其家人。

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

我現在將電話轉給詹姆斯·漢密爾頓博士。

Thank you, Andy. With our sharpened focus on the cardiometabolic therapeutic area, I'd like to discuss our two new programs for our obesity and metabolic disease. Clearly, there have been advancements in the obesity space of late. This has created excitement in the field, and we believe our programs, ARO-INHBE and ARO-ALK7 have attractive profiles and may fill gaps in the current standard of care.

謝謝你，安迪。隨著我們對心臟代謝治療領域的更加關注，我想討論我們針對肥胖和代謝疾病的兩個新計劃。顯然，肥胖領域最近取得了進展。這引起了該領域的興奮，我們相信我們的專案 ARO-INHBE 和 ARO-ALK7 具有有吸引力的特徵，可能會填補當前護理標準的空白。

We held a webinar in August on the obesity and metabolic space as part of our summer series of R&D webinars. We covered the biology of these targets, our pre-clinical data and our clinical plans. That presentation is still available as an archive on the website.

作為我們夏季系列研發網路研討會的一部分，我們在八月舉辦了一次關於肥胖和代謝空間的網路研討會。我們介紹了這些標靶的生物學、我們的臨床前數據和我們的臨床計劃。此簡報仍可在網站上作為存檔使用。

As a high-level refresher activation of the INHBE/ALK7 pathway instructs adipocytes to store fat. In an environment of nutrient excess, this pathway can become dysfunctional and overactive. Both targets are supported by human genetics, where loss of function carriers have favorable body composition and metabolic characteristics compared to non-carriers. ARO-INHBE is a GalNAc-siRNA conjugate intended to silence hepatic INHBE expression. INHBE's mRNA codes for active protein, which is one of the ligands binding to ALK7 on the adipocyte surface.

作為高級複習，INHBE/ALK7 通路的活化指示脂肪細胞儲存脂肪。在營養過剩的環境中，該途徑可能會變得功能失調和過度活躍。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有利的身體組成和代謝特徵。 ARO-INHBE 是一種 GalNAc-siRNA 綴合物，旨在沉默肝臟 INHBE 表現。 INHBE 的 mRNA 編碼活性蛋白，它是與脂肪細胞表面 ALK7 結合的配體之一。

It's the expression of ALK7 mRNA that is targeted with ARO-ALK7, which uses Arrowhead's novel adipocyte siRNA delivery platform. ARO INHBE and ARO-ALK7 achieved 22% and 50% reduction in fat mass, respectively, versus saline controls in a mouse diet-induced obesity model. Importantly, this is achieved with the preservation of lean mass. In the same mouse model, when studied in combination with incretin therapy, inhibition of the INHBE/ALK7 pathway can potentiate weight loss with lower doses of incretin therapy while simultaneously preserving lean mass.

ARO-ALK7 的目標是 ALK7 mRNA 的表達，ARO-ALK7 使用 Arrowhead 的新型脂肪細胞 siRNA 遞送平台。在小鼠飲食誘發的肥胖模型中，與生理食鹽水對照組相比，ARO INHBE 和 ARO-ALK7 的脂肪量分別減少了 22% 和 50%。重要的是，這是透過保留瘦體重來實現的。在同一小鼠模型中，當與腸促胰島素治療聯合進行研究時，抑制 INHBE/ALK7 路徑可以透過較低劑量的腸促胰島素治療增強體重減輕，同時維持瘦體重。

Again, for those interested, I refer you to our August obesity and metabolic R&D webinar for more pre-clinical data details. Turning to the clinical studies planned for these molecules, both Phase I studies will evaluate single and multiple ascending doses as a monotherapy in obese patients as well as multiple doses in obese patients with or without type 2 diabetes in combination with incretin therapy. ARO-INHBE dosing should initiate very soon and dosing with ARO-ALK7 should initiate in 2025. We look forward to providing updates on these studies throughout 2025.

同樣，對於有興趣的人，我建議您參加我們的八月份肥胖和代謝研發網路研討會，以獲取更多臨床前數據詳細資訊。談到這些分子計畫的臨床研究，兩項I 期研究將評估單次和多次遞增劑量作為肥胖患者的單一療法，以及與腸促胰島素治療聯合治療患有或不患有2 型糖尿病的肥胖患者的多次劑量。 ARO-INHBE 給藥應很快開始，ARO-ALK7 給藥應於 2025 年開始。

I will now turn the call over to Ken Myszkowski.

我現在將把電話轉給 Ken Myszkowski。

Thank you, James, and good afternoon, everyone. As we reported today, our net loss for fiscal 2024 was $599.5 million or $5 per share based on $119.8 million fully diluted weighted average shares outstanding. This compares with a net loss of $205.3 million or $1.92 per share based on $106.8 million fully diluted weighted average shares outstanding for 2023.

謝謝詹姆斯，大家下午好。正如我們今天報道的，我們 2024 財年的淨虧損為 5.995 億美元，即每股 5 美元，基於 1.198 億美元的完全稀釋加權平均已發行股票計算。相較之下，根據 2023 年 1.068 億美元的完全稀釋加權平均流通股計算，淨虧損為 2.053 億美元，即每股 1.92 美元。

Revenue in 2024 was $3.6 million as there were no new partnership or license agreements executed during the year and no major milestones from previous license agreements were triggered during 2024. Revenue in 2023 was $240.7 million, Revenue in 2023 primarily relates to our collaboration agreements with Takeda, GSK, and Amgen.

2024 年收入為360 萬美元，因為年內沒有執行新的合作夥伴關係或授權協議，且2024 年沒有觸發先前授權協議的重大里程碑。合作協議有關、葛蘭素史克和安進。

Total operating expenses for fiscal 2024 were $604.6 million compared to $445.7 million for 2023, an increase of $158.9 million. In 2024, operating expenses, excluding non-cash stock compensation charges and depreciation and amortization, a better indicator of cash spend were $512.1 million compared to $355.1 million in 2023, an increase of $157 million. The key drivers of this change were increased research and development costs, primarily candidate costs, which is driven by clinical costs, manufacturing costs, and toxicology costs. In particular, during the third fiscal quarter, we kicked off certain large Phase 3 clinical trials for our drug candidate plozasiran to address further indications beyond FCS, namely severe hypertriglyceriyceridemia or SHTG.

2024 財年的總營運支出為 6.046 億美元，比 2023 年的 4.457 億美元增加了 1.589 億美元。 2024 年，不包括非現金股票補償費用以及折舊和攤銷（更好的現金支出指標）的營運支出為 5.121 億美元，與 2023 年的 3.551 億美元相比，增加了 1.57 億美元。這項變化的關鍵驅動因素是研發成本增加，主要是候選成本，這是由臨床成本、製造成本和毒理學成本所驅動的。特別是，在第三財季，我們啟動了候選藥物 plozasiran 的某些大型 3 期臨床試驗，以解決 FCS 以外的進一步適應症，即嚴重高三酸甘油酯血症或 SHTG。

Net cash used in operating activities during fiscal 2024 was $462.9 million compared with net cash used in operating activities of $153.9 million in 2023. The increase in cash used in operating activities is driven primarily by higher research and development expenses as well as lower revenue versus the prior year.

2024 財年經營活動使用的現金淨額為 4.629 億美元，而 2023 年經營活動使用的現金淨額為 1.539 億美元。一年。

Our footprint expansion is complete with only minor final payments to be made over the next few months totaling $8 million. We expect very little capital expenditures in fiscal 2025.

我們的足跡擴張已經完成，只需在接下來的幾個月內支付總計 800 萬美元的小額最終付款。我們預計 2025 財年的資本支出非常少。

Turning to our balance sheet. Our cash and investments totaled $681 million at September 30, 2024, compared to $403.6 million at September 30, 2023. The increase in our cash and investments was primarily related to the $450 million equity issuance as well as the $400 million debt facility, partially offset by ongoing cash burn.

轉向我們的資產負債表。截至2024 年9 月30 日，我們的現金和投資總額為6.81 億美元，而截至2023 年9 月30 日為4.036 億美元。美元的債務融資有關，部分抵消了透過持續的現金消耗。

We expect our largest cash expenditure in 2025 to be related to the Phase 3 studies for plozasiran. We expect that costs for the ongoing studies will start to decrease in '26 and '27. Thus, a large portion of those study costs were incurred in 2024 as start-up costs, in 2025 as ramp-up costs, which then start to decrease in 2026. Our other clinical studies are earlier phase studies, which require much less capital.

我們預計 2025 年最大的現金支出將與 plozasiran 的 3 期研究有關。我們預計正在進行的研究的成本將在 26 年和 27 年開始下降。因此，這些研究成本的很大一部分在 2024 年作為啟動成本產生，在 2025 年作為啟動成本產生，然後在 2026 年開始減少。

The collaboration agreement with Sarepta brings in $500 million in upfront cash, $325 million as an equity investment priced at $27.25 per share representing a 35% premium to the 30-day volume weighted average price and additional near-term cash of $350 million. Pro forma cash resources at September 30, 2024, including just the upfront cash and equity investment would be $1.5 billion.

與 Sarepta 的合作協議帶來 5 億美元的預付現金、3.25 億美元的股權投資（每股 27.25 美元），較 30 天成交量加權平均價溢價 35%，以及 3.5 億美元的額外近期現金。截至 2024 年 9 月 30 日，預計現金資源（僅包括前期現金和股權投資）將為 15 億美元。

We estimate that this partnership agreement extends our cash runway into 2028, during which time we expect plozasiran may be approved for the additional indication of SHTG. This capital significantly enhances our balance sheet and puts us on very solid financial footing for several years.

我們估計這項合作協議將我們的現金跑道延長至 2028 年，在此期間我們預計 plozasiran 可能會被批准用於 SHTG 的額外適應症。這筆資本顯著增強了我們的資產負債表，並使我們在未來幾年內擁有非常堅實的財務基礎。

Turning to financial guidance. We expect total cash burn in fiscal 2025 to be $500 million to $550 million, of which about $62 million to $65 million is related to G&A costs. We expect a similar cash burn in 2026, with G&A comprising about $65 million of spend.

轉向財務指導。我們預計 2025 財年的現金消耗總額將為 5 億至 5.5 億美元，其中約 6,200 萬至 6,500 萬美元與一般管理費用相關。我們預計 2026 年也會出現類似的現金消耗，其中 G&A 支出約為 6,500 萬美元。

Incorporating debt repayments and cash inflows, we expect our cash balance at the end of 2025 to be about $1 billion, and we expect our cash balance at the end of 2026 to be between $600 million and $650 million.

考慮到債務償還和現金流入，我們預計 2025 年底的現金餘額約為 10 億美元，預計 2026 年底的現金餘額將在 6 億至 6.5 億美元之間。

We believe our cash runway extends into 2028. These estimates include modest revenue for FCS but do not include potential revenue from future business development deals. So if these assumptions prove overly conservative, our cash balances may be higher. Our common shares outstanding at September 30, 2024, were $124.4 million.

我們相信我們的現金跑道會延伸到 2028 年。因此，如果這些假設被證明過於保守，我們的現金餘額可能會更高。截至 2024 年 9 月 30 日，我們已發行的普通股為 1.244 億美元。

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

簡單概述後，我現在將把電話轉回給克里斯。

Thanks, Ken. As I mentioned, Arrowhead is now extraordinarily well positioned to build value in the short, medium and long term. We think all the necessary pieces are in place to execute effectively and efficiently. We are funded into 2028 with additional non-dilutive funding expected with existing and potentially new partnerships advance through clinical studies and generate commercial products.

謝謝，肯。正如我所提到的，Arrowhead 現在處於非常有利的位置，可以在短期、中期和長期創造價值。我們認為所有必要的部分都已到位，可以有效且有效率地執行。到 2028 年，我們將獲得額外的非稀釋資金，預計現有的和潛在的新合作夥伴關係將透過臨床研究推進並產生商業產品。

We are building out commercial to be ready on day one for our first commercial launch of plozasiran in patients with genetically confirmed or clinically diagnosed FCS. We are eager to receive our PDUFA date from FDA, but our expectation for commercial planning purposes is to be ready to launch in the middle of 2025.

我們正在開發商業產品，以便在第一天為我們在基因確診或臨床診斷的 FCS 患者中首次商業推出 plozasiran 做好準備。我們渴望收到 FDA 的 PDUFA 日期，但出於商業規劃目的，我們的期望是準備在 2025 年中期推出。

Plozasiran, our lead program is also in Phase 3 studies to potentially expand into the large and significantly underserved SHTG population a couple of years after we launch in FCS. If successful, that would provide a potentially large revenue stream. Aside of plozasiran, we have focused our pipeline around a cluster of cardiometabolic programs, providing some mid-term opportunities for commercial launches and multiple long-term opportunities. We also retain select key early-stage programs, providing opportunities to build pipeline value while still managing to limit growth in R&D expense.

Plozasiran，我們的主導計畫也處於第 3 階段研究，在我們在 FCS 推出幾年後，有可能擴展到大量且服務嚴重不足的 SHTG 族群。如果成功，這將提供潛在的巨大收入來源。除了 plozasiran 之外，我們的產品線還集中在一系列心臟代謝項目上，為商業啟動提供一些中期機會和多個長期機會。我們也保留精選的關鍵早期項目，提供建立管道價值的機會，同時仍設法限制研發費用的成長。

Lastly, we have a new collaboration partner with extensive clinical, regulatory, and commercial expertise to advance and commercialize multiple promising candidates outside of our cardiometabolic commercial focus. So we end fiscal 2024 in a strong position across the board and are now well positioned to execute on our long-term strategy and bring several important new medicines to patients over the coming years.

最後，我們有一個新的合作夥伴，擁有廣泛的臨床、監管和商業專業知識，可以在我們的心臟代謝商業重點之外推進和商業化多個有前途的候選藥物。因此，到 2024 財年結束時，我們在各方面都處於強勢地位，現在已經準備好執行我們的長期策略，並在未來幾年為患者帶來幾種重要的新藥。

Thank you for joining us today, and I would now like to open the call to your questions. Operator?

感謝您今天加入我們，現在我想開始回答您的問題。操作員？

Thank you. (Operator Instructions)

謝謝。 （操作員說明）

Ellie Merle, UBS.

艾莉·梅爾，瑞銀。

Hi, this is Jasmine on for Ellie. Thanks so much for taking our question and congratulations on all the progress. So first, just with the deal with Sarepta, including a few FC programs in Huntington's with the subcu delivery, how are you thinking about the future of Arrowhead's CNS franchise from here and particularly where else you'd like to go with the subcu delivery? And then second, just curious on anything you can say about future plans for zodasiran. Thanks.

大家好，我是艾莉的茉莉花。非常感謝您提出我們的問題並祝賀所有的進展。首先，就與 Sarepta 的交易而言，包括亨廷頓的一些 FC 項目以及 subcu 交付，您如何看待 Arrowhead 的 CNS 特許經營權的未來，特別是您還想在哪裡進行 subcu 交付？其次，只是好奇你能對 zodasiran 的未來計畫說些什麼。謝謝。

Sure. So thanks very much for the question. So the subcu CNS platform is one that we're really excited about. As you mentioned, HTT will go to Sarepta. We also have MAPT and alpha-synuclein that we are developing that remain wholly owned, as I mentioned in the prepared remarks.

當然。非常感謝您提出的問題。所以 subcu CNS 平台是我們真正興奮的一個。正如您所提到的，HTT 將前往 Sarepta。正如我在準備好的演講中提到的，我們還有正在開發的 MAPT 和 α-突觸核蛋白，它們仍然是全資擁有的。

Those are not really core to our business, and so those are potentially partnerable at some point. We are trying to determine the optimal time to partner those.

這些並不是我們業務的真正核心，因此在某些時候它們可能是可以合作的。我們正在努力確定與這些人合作的最佳時間。

We see a number of good potential CNS targets in the cardiometabolic basin. So I do expect that we will develop and retain some wholly owned CNS assets that will be, again, core to our cardiometabolic business. So stay tuned on that. I expect that we'll have some updates on that in 2025.

我們在心臟代謝盆地中看到了許多良好的潛在中樞神經系統標靶。因此，我確實希望我們將開發並保留一些全資中樞神經系統資產，這些資產將再次成為我們心臟代謝業務的核心。所以請繼續關注。我預計我們會在 2025 年對此進行一些更新。

Regarding zodasiran, we are trying to figure out our strategy there. At the very least, we see a big opportunity or at least an interesting opportunity in HoFH. And so we have a protocol waiting to go -- waiting to start for a Phase 3 study to support HoFH. And we are also exploring how else we may be able to exploit that asset.

關於zodasiran，我們正在努力製定我們的策略。至少，我們在 HoFH 看到了一個巨大的機會，或者至少是一個有趣的機會。因此，我們有一個方案正在等待實施——等待開始支持 HoFH 的第三階段研究。我們還在探索如何利用該資產。

Luca Issi, RBC Capital.

盧卡·伊西，加拿大皇家銀行資本。

Great. Thanks so much for taking my question. Congrats on the progress and obviously on the deal with Sarepta. Maybe two quick ones. Bruce, if I may, we've seen Eli Lilly discontinuing their siRNA for APOC3. So wondering what was your reaction to that.

偉大的。非常感謝您提出我的問題。恭喜所取得的進展，當然也恭喜與 Sarepta 的交易。也許兩個快點。 Bruce，如果可以的話，我們已經看到 Eli Lilly 停止了針對 APOC3 的 siRNA。所以想知道你對此有何反應。

And then maybe on the deal, Chris, can you just maybe provide any color on whether that deal with Sarepta was competitive? And then maybe related, lots of moving parts, obviously, with the FTC, but any potential risk here in the context of what we saw a year ago between Sanofi and Maze? Any color there? Much appreciated. Thanks so much, guys.

然後，也許在這筆交易上，克里斯，你能否提供一些關於與 Sarepta 的交易是否具有競爭力的信息？然後可能與聯邦貿易委員會有關，顯然有很多移動部件，但是在我們一年前看到的賽諾菲和 Maze 之間的情況下，這裡有任何潛在的風險嗎？有顏色嗎？非常感謝。非常感謝，夥計們。

Sure, Bruce. Why don't you take yours first, and then I'll go after that.

當然，布魯斯。為什麼不先拿你的，然後我再去。

Sure. I, of course, don't know why Lilly made that decision. It's hard to assess from a distance -- plozasiran is an awfully good drug. And it may have set the bar too high; that's a possibility. But I really can't determine why Lilly would have made that decision one way or the other. Not very fulfilling for you, I know but that's about the best I could do.

當然。當然，我不知道莉莉為什麼會做出這個決定。很難從遠處評估——plozasiran 是一種非常好的藥物。它可能把標準定得太高了；這是一種可能性。但我真的無法確定為什麼莉莉會以這種或那種方式做出這個決定。我知道這對你來說不太令人滿意，但這就是我能做的最好的了。

All right. And thanks for the questions, Luca. So regarding my question. So was the Sarepta deal competitive? Sure. We were talking to other companies about large strategic deals. This one made sense to us. There's, of course, never 100% overlap with respect to what's included in these various strategic deals, but at least philosophically, we were talking to other companies about that.

好的。謝謝你的提問，盧卡。關於我的問題。那麼 Sarepta 交易是否具有競爭力？當然。我們正在與其他公司討論大型策略交易。這對我們來說很有意義。當然，這些不同的策略交易中的內容永遠不會 100% 重疊，但至少從哲學上來說，我們正在與其他公司討論這一點。

And look, the potential good news here is that we also have additional assets I mentioned in the prepared remarks that remain unpartnered that are not core to our business. And so I think we have room to do additional partnerships.

看，這裡潛在的好消息是，我們還有我在準備好的評論中提到的其他資產，這些資產仍然是非合作夥伴，不是我們業務的核心。因此，我認為我們還有開展更多合作的空間。

Nothing -- I don't think quite as large as what we're talking about here with Sarepta with an overall deal value greater than $11 billion plus royalties, but I think there are still good deals we can do with other companies or on other assets, potentially with discovery components. As I mentioned, we've got an extraordinarily productive discovery team that has capacity to serve us and Sarepta as well as other partners.

沒什麼——我認為沒有我們在這裡談論的 Sarepta 那麼大，總交易價值超過 110 億美元加上特許權使用費，但我認為我們仍然可以與其他公司或其他公司達成良好的交易資產，可能帶有發現組件。正如我所提到的，我們擁有一支非常有效率的發現團隊，有能力為我們、Sarepta 以及其他合作夥伴提供服務。

Regarding the HSR risk, look, who knows? I can't give you much guidance on that other than from our perspective, there does not seem to be overlap there that make us concerned. But of course, that's not our call to make. We'll just have to see when that comes down. We expect to have a ruling 30 days after we file. And so sometime in, I believe, early January is when we would expect to clear HSR.

關於高鐵風險，誰知道呢？除了從我們的角度來看，我無法給你太多指導，那裡似乎沒有讓我們擔心的重疊。但當然，這不是我們的決定。我們只需要看看什麼時候會發生。我們預計在提交申請後 30 天做出裁決。因此，我相信，一月初的某個時候，我們預計會批准高鐵。

Andrea Newkirk, Goldman Sachs.

安德里亞·紐柯克，高盛。

Hi, everyone. Thanks for taking my question and congratulations on the deal. Maybe on the back of that, and in the context of the debt financing that you announced on the last earnings call, how are you thinking about paying that down? And is there a particular amount that's maybe earmarked in the Sarepta deal that's obligated towards paying off the principal for that facility?

大家好。感謝您提出我的問題並祝賀這筆交易。也許在此背景下，在您在上次財報電話會議上宣布的債務融資背景下，您如何考慮償還債務？ Sarepta 交易中是否指定了一筆特定金額，用於償還該設施的本金？

And then Ken maybe a question for you here. If you could quantify the R&D savings that you expect to realize and over what time period we could think about that. Thanks so much.

肯可能會問你一個問題。如果您可以量化您期望實現的研發節省以及在什麼時間段內我們可以考慮這一點。非常感謝。

Sure. So we will be paying down the debt you know through Sarepta as well as through other deals as cash comes in. There are formulas for that. And so we do expect that to contribute to paying down the debt over time.

當然。因此，隨著現金的到來，我們將透過 Sarepta 以及其他交易來償還你們所知的債務。因此，我們確實希望隨著時間的推移，這將有助於償還債務。

So we've taken certain costs out of the budget, but the main components or the biggest part of our R&D spend relates to those three Phase 3 trials that I mentioned earlier, and we expect those costs to continue over the next two years and then decrease by 2027. So it would depend on if there's any new large trials by that time. But over the next two years, we'd expect it to remain constant with the guidance and then decrease.

因此，我們已經從預算中扣除了某些成本，但我們研發支出的主要組成部分或最大部分與我之前提到的那三個三期試驗有關，我們預計這些成本將在未來兩年內持續存在，然後到 2027 年會減少。但在接下來的兩年裡，我們預計它會與指導保持一致，然後下降。

(Operator Instructions)

（操作員說明）

Maury Raycroft, Jeffreries.

莫里‧雷克羅夫特，傑弗里斯。

Hi, thanks for taking my questions and congrats on the deal update today. Wanted to ask about the obesity programs. So for INHBE and ALK7, how important are the strategically to the company at this point? And with obesity studies, you can get insight into efficacy relatively quickly. Wondering if you'll run a placebo-controlled Phase 1? And can you commit to getting to data from either of these programs sometime next year?

您好，感謝您回答我的問題，並祝賀今天的交易更新。想詢問有關肥胖計劃的問題。那麼對於 INHBE 和 ALK7 來說，目前對公司的策略有多重要？透過肥胖研究，您可以相對快速地了解功效。想知道您是否會進行安慰劑對照的第一階段？您能否承諾在明年某個時候從這兩個項目中獲取數據？

I'll take the strategic question. These are important to us strategically. Look, these are really interesting targets, genetically validated. We will be, I believe, the first ones in the clinic with INHBE, and I think we will be the first one in the clinic by a long shot with ALK7. I don't know anybody else will be in the clinic in the near term with siRNA against adipose.

我來回答戰略問題。這些對我們來說具有戰略意義。看，這些都是非常有趣的目標，經過基因驗證。我相信，我們將成為第一批進入臨床的 INHBE 患者，我認為我們也將成為第一批進入臨床的 ALK7 患者。我不知道短期內還有其他人會在診所使用針對脂肪的 siRNA。

So we like our positioning here. We like the genetic data. We love our animal data. And so these are important for us.

所以我們喜歡我們在這裡的定位。我們喜歡遺傳數據。我們喜歡我們的動物數據。所以這些對我們來說很重要。

To be honest, if we wanted to partner these, we could have. But these are important for us strategically. And so we look forward to run these studies and see what we see.

老實說，如果我們想與這些合作，我們可以這樣做。但這些對我們來說具有戰略意義。因此，我們期待著進行這些研究並看看我們會看到什麼。

James, do you want to address the Phase 1.

詹姆斯，你想談談第一階段嗎？

Sure. Yeah. On the Phase 1 designs, both programs are placebo-controlled in patients with obesity. The main purpose of the study are, of course, to generate an understanding around safety and PK and some early target engagement biomarker data. I mean we have some exploratory end points in there, but these are primarily focused on safety, PK, and biomarkers.

當然。是的。在第一階段的設計中，這兩個項目都是針對肥胖患者的安慰劑對照。當然，研究的主要目的是加深對安全性和 PK 以及一些早期標靶參與生物標記數據的了解。我的意思是，我們有一些探索性終點，但這些終點主要集中在安全性、PK 和生物標記上。

Jason Gerberry, Bank of America.

傑森‧格伯里，美國銀行。

Hi, good afternoon. This is Dina on for Jason. Thanks for taking our question. Congrats on the deal announcement and the progress this quarter. The first one we had is more of a broad strokes question, how does the Sarepta agreement than your TRiM discovery engine prioritization by tissue type and targeted number of lead pre-clinical candidates that you plan to kind of accelerate into the IND stage over the near term? Like do you plan to kind of separately advance pre-clinical assets for your own internal verticals or for additional partnerships?

嗨，下午好。這是迪娜為傑森代言的。感謝您提出我們的問題。祝賀交易公告和本季的進展。我們遇到的第一個問題是一個更廣泛的問題，與您的TRiM 發現引擎相比，Sarepta 協議如何按組織類型和主要臨床前候選藥物的目標數量進行優先排序，您計劃在近期加速進入IND 階段學期？例如您是否計劃為自己的內部垂直領域或其他合作夥伴單獨推進臨床前資產？

And then I just had a follow-up on your zodasiran strategy. Is it maybe safe to say that we could see an execution of a COVT (sic – CVOT) when the company is in a better capital position with costs from the plozasiran studies winding down in 2026 or so? Thank you.

然後我剛剛對你的 Zodasiran 策略進行了跟進。是否可以肯定地說，當公司處於更好的資本狀況並且 plozasiran 研究的成本在 2026 年左右逐漸減少時，我們可以看到 COVT（原文如此 – CVOT）的執行？謝謝。

So with respect to the CVOT question, look, we have always been interested in asking the triglyceride question in outcomes, and our KOLs feel strongly that plozasiran could be a very powerful ASCVD drug. And so we just need to wait to see better visibility on capital in order to start that CVOT. Those can be expensive and time-consuming. And so we just want to make sure that we've got the capital in front of us before we start that.

因此，關於 CVOT 問題，我們一直有興趣詢問結果中的三酸甘油酯問題，我們的 KOL 強烈認為 plozasiran 可能是一種非常強大的 ASCVD 藥物。因此，我們只需要等待看到更好的資本可見性即可啟動 CVOT。這些可能既昂貴又耗時。因此，我們只是想確保在開始之前我們已經擁有了資金。

With respect to the first question, sorry, what was that again?

關於第一個問題，抱歉，那又是什麼？

Our bandwidth for -- target (multiple speakers)

我們的頻寬目標（多位發言者）

Yeah, right. So look, on discovery, we really can be an and company, not an or company. We've got plenty of bandwidth to serve Sarepta and to serve ourselves and frankly, to serve other partners. James, approximately how many nominations can we do over the last couple of years?

是的，對。所以你看，經過發現，我們確實可以成為一家「與」公司，而不是「與」公司。我們有足夠的頻寬來服務 Sarepta 和我們自己，坦白說，也可以服務其他合作夥伴。詹姆斯，過去幾年我們大約可以提名多少次？

I mean we've done close to double-digit nominations per year. So 5 to 10 per year is certainly doable, and all of the targets will probably not come in all at once from a partner.

我的意思是我們每年的提名數量接近兩位數。因此，每年 5 到 10 個目標當然是可行的，而且所有目標可能不會一次全部由合作夥伴提出。

Right. So if we are in the 5 to 10 nomination range per year, this is a five-year collaboration. And so over those five years, we could -- goodness, we'll have dozens and dozens of nominations over the time. We've got plenty of room to have a vigorous discovery campaign for ourselves as well as Sarepta as well as for other partners.

正確的。因此，如果我們每年獲得 5 到 10 名提名，那麼這就是一個為期五年的合作。因此，在這五年裡，我們可以——天哪，我們將獲得數十個提名。我們有足夠的空間來為我們自己、Sarepta 以及其他合作夥伴進行積極的發現活動。

Patrick Trucchio, H.C. Wainwright

特魯基奧 (Patrick Trucchio)，H.C.溫賴特

Thanks and good afternoon. And congrats on the collaboration. I just have a couple of follow-ups on it. Can you tell us how the clinical or pre-clinical programs are expected to be prioritized within the collaboration with Sarepta and how much input Arrowhead would expect to have in that process? And separately, can you tell us how the collaboration contributes to or accelerates achieving the 2025 strategy?

謝謝，下午好。並祝賀雙方合作。我對此只有一些後續行動。您能否告訴我們，在與 Sarepta 的合作中，臨床或臨床前計畫預計將如何確定優先順序，以及 Arrowhead 預計在此過程中獲得多少投入？另外，您能否告訴我們此次合作如何有助於或加速實現 2025 年策略？

Sure. So I'll take that one first. I don't know that it affects our 2025 strategy so much, because we have one more year for 2025. I don't know if Sarepta can move fast enough to get us to target and for us to get them something that will enter the clinic during that time. So I don't think it's relevant to 2025 necessarily.

當然。所以我先拿那個。我不知道這對我們的2025 年策略影響如此之大，因為2025 年我們還有一年的時間。 我不知道Sarepta 是否能夠足夠快地行動，讓我們達到目標，並讓我們為他們提供一些可以進入市場的東西。所以我認為這與 2025 年沒有必然關係。

Regarding prioritization or regarding how we run those, well, so let's see -- so the clinical assets will go to them. We are happy to help them with the transition, but those will ostensively move to them, and they will continue those clinical programs essentially on day one, again. We're happy to help them, but that will be their purview.

關於優先順序或關於我們如何運行這些，好吧，讓我們看看 - 這樣臨床資產就會流向他們。我們很高興能幫助他們完成過渡，但這些表面上會轉移給他們，他們將在第一天再次繼續這些臨床計畫。我們很樂意幫助他們，但這將是他們的職權範圍。

The non-clinical assets, we will get those two CTA-ready and then they will take those over and assume all the cost and, of course, all the burden of running clinical studies with them. Same thing with the discovery bucket. Our job is to get them a CTA-ready package, and then they would take those for you in the clinic.

對於非臨床資產，我們將準備好這兩個 CTA，然後他們將接管這些資產並承擔所有成本，當然還有用它們進行臨床研究的所有負擔。發現桶子也是如此。我們的工作是為他們提供 CTA 準備好的包裹，然後他們會在診所為您取走這些包裹。

Edward Tenthoff, Piper Sandler.

愛德華·騰索夫，派珀·桑德勒。

Great. Thank you. My congrats to you on the financing. You guys have been wheeling and dealing, and I love to see it. When it comes to the $250 million over the five-year period, firstly, is that considered like an R&D funding? Or what is sort of the classification of that? And how will that be -- is that just straight line amortized? Or how would you be recognizing that?

偉大的。謝謝。我祝賀您獲得融資。你們一直在搞交易，我很高興看到這樣的情況。說到五年期間的2.5億美元，首先，這算不算研發經費？或者說它的分類是什麼？那會怎樣──這只是直線攤銷嗎？或者你會如何體認到這一點？

So the $250 million payment was just a timing of the payment. The accounting recognition -- the revenue recognition for that, we need to assess that with the rest of the deal, including the upfront payment and what our performance obligations are. So we'll get more information to you on how we will recognize that revenue.

所以2.5億美元的付款只是付款的時間點。會計確認－收入確認，我們需要與交易的其餘部分一起評估，包括預付款和我​​們的履約義務。因此，我們將向您提供有關如何確認該收入的更多資訊。

And that's simply $50 million a year over five years of starting on the one-year anniversary of the closing of the deal.

這只是從交易完成一週年開始算起的五年內每年 5,000 萬美元。

Mayank Mamtani, B. Riley Securities.

Mayank Mamtani，B. Riley 證券。

Yes. Good afternoon. Thanks for taking our question and congrats on a productive quarter and the deal. Just quickly following up on the plozasiran NDA filing strategy, could you confirm that the focus there is on the 25 mg dose level? And how do you think of the total patient exposure there to be able to have that broader label that you did evaluate the study for with and without FCS you get from patients? And I do have a follow-up.

是的。午安.感謝您提出我們的問題，並祝賀本季富有成果並達成交易。快速跟進 plozasiran NDA 申請策略，您能否確認重點是 25 毫克劑量等級？您如何看待患者的總暴露量，以便能夠獲得更廣泛的標籤，就像您評估研究時從患者那裡獲得的有或沒有 FCS 的情況一樣？我確實有後續行動。

Bruce?

布魯斯？

Well, so the filing is only for the 25-milligram dose, because it performed really at least equally to the 50-milligram dose. So as I said, all the data for the drug and all the indications said 25 milligrams was the right dose. So I think we're very -- we feel very solid there.

好吧，所以備案僅適用於 25 毫克劑量，因為它的性能至少與 50 毫克劑量相同。正如我所說，該藥物的所有數據和所有適應症都表明 25 毫克是正確的劑量。所以我認為我們在那裡感覺非常穩固。

The question -- if I understood the second question right; I didn't really hear it very well. But if I understood it correctly, we, of course, don't know at this point the agency, how the FDA will feel about the question of genetic versus clinical FCS. We did expand to include the clinically diagnosed FCS patients at the suggestion of the agency. So that's something.

問題——我是否正確理解了第二個問題；我真的沒聽清楚。但如果我理解正確的話，我們當然不知道 FDA 目前對遺傳 FCS 與臨床 FCS 的問題有何看法。根據該機構的建議，我們確實將臨床診斷的 FCS 患者納入其中。所以就是這樣。

But ultimately, we would assume that, assuming the agency is happy with the NDA in the end, we won't be discussing indication until the very end. I hope I answered your question there, but I'm not 100% sure I did.

但最終，我們會假設，假設該機構最終對 NDA 感到滿意，我們直到最後才會討論指示。我希望我在那裡回答了你的問題，但我不能 100% 確定我回答了。

Prakhar Agarwal, Cantor.

普拉哈·阿加瓦爾，康托爾。

Thank you for taking my questions and congrats on the Sarepta deal. Maybe firstly, on the deal, how much of the data did Sarepta see on both DM1 and FSHD programs? Was it mostly limited to the SAT programs -- SAT cohorts? Or were you able to see some of the multiple those data as well?

感謝您回答我的問題，並祝賀 Sarepta 達成交易。也許首先，在這筆交易中，Sarepta 在 DM1 和 FSHD 專案上看到了多少資料？是否主要侷限於 SAT 計畫－SAT 群體？或者您也能看到其中的一些數據嗎？

And second question is on INHBE. It's an interesting target -- pre-clinical data, very interesting and the genetic evidence is out there. So maybe just broadly, how are you thinking about where this drug fits a new [BT] landscape relative to incretins out there commercially and that are coming out soon? And how does the RNAi therapy differentiate in obesity? Thank you.

第二個問題是關於 INHBE 的。這是一個有趣的目標——臨床前數據，非常有趣，而且遺傳證據就在那裡。因此，也許從廣義上講，您如何看待這種藥物相對於商業化且即將上市的腸降血糖素而言適合新的 [BT] 領域？ RNAi 療法如何區分肥胖症？謝謝。

Sure. So Sarepta side we have not moved into MAD cohorts yet. So all we have is very limited, in fact, SAD data, but that's what they saw.

當然。因此，Sarepta 方面我們還沒有進入 MAD 佇列。所以我們擁有的實際上是非常有限的 SAD 數據，但這就是他們看到的。

Regarding INHBE and ALK-7, look, our job here is not necessarily to put GLP-1s out of business. I think that we have an opportunity to work with GLP-1s as we talked about in the prepared remarks and also in the webinar several months ago. At least in animal studies, we were able to use a sub-therapeutic dose of tirzepatide in combination with either ALK7 or INHBE and show good weight loss, in fact, better quality weight loss than tirzepatide alone.

關於 INHBE 和 ALK-7，我們的工作不一定是讓 GLP-1 破產。我認為我們有機會與 GLP-1 合作，正如我們在準備好的演講中以及幾個月前的網路研討會中所討論的那樣。至少在動物研究中，我們能夠將亞治療劑量的替澤帕肽與 ALK7 或 INHBE 聯合使用，並顯示出良好的減肥效果，事實上，比單獨使用替澤帕肽的減肥品質更好。

That could be a possible use, and also maintenance could be a possible use in order to be on a GLP-1 and then lose a substantial amount of weight and then keep it off with INHBE or ALK7. They can also be used as monotherapy; who knows? And we'll see what the tolerability looks like.

這可能是一種可能的用途，維護也可能是一種可能的用途，以便使用 GLP-1，然後減輕大量體重，然後使用 INHBE 或 ALK7 保持體重。它們也可以用作單一療法；誰知道？我們將看看耐受性如何。

From our perspective, as you say, the non-clinical data were compelling. The genetic data are compelling. And so we really look forward to seeing how this translates into humans.

從我們的角度來看，正如您所說，非臨床數據是令人信服的。遺傳數據令人信服。所以我們真的很期待看到這如何轉化為人類。

David Lebowitz, Citi.

大衛‧勒博維茨，花旗銀行。

Thank you very much for taking my question. Given the large partnership with Sarepta, what are your thoughts on additional partnerships going forward? Are you intending to take a pause from that? Or are you still on the lookout?

非常感謝您回答我的問題。鑑於與 Sarepta 的廣泛合作，您對未來更多合作有何看法？你打算暫停一下嗎？還是你還在觀望？

I would say somewhere in between those. We are still on the lookout. As I mentioned, we were -- before we did the Sarepta deal, we were in discussions with other companies about large strategic collaborations. Those we are no longer really considering, but there are smaller bite-sized collaborations and license agreements that certainly could take place.

我想說介於兩者之間。我們仍在觀察。正如我所提到的，在完成 Sarepta 交易之前，我們正在與其他公司討論大型策略合作。我們不再真正考慮這些，但肯定可以進行較小規模的合作和授權協議。

Look, our hair is not on fire. This is an important deal for us. This gives us a lot of breathing room and gives us, frankly, what we needed in a number of areas. And so I think we can get the right deal or deals done over time. We don't have to have that tomorrow. But I do expect more deals over some period of time.

看，我們的頭髮沒有著火。這對我們來說是一筆重要的交易。這給了我們很大的喘息空間，坦白說，這給了我們在許多領域所需要的東西。因此，我認為隨著時間的推移，我們可以達成一項或多項正確的交易。我們明天不必這樣。但我確實預計在一段時間內會有更多交易。

Certainly, we've got the capacity on the discovery side. And we've got the assets, both non-clinical and clinical that are not core to our metabolic -- to our cardiometabolic focus. And so I think there's ample ammunition there for additional deals.

當然，我們有發現方面的能力。我們擁有非臨床和臨床資產，這些資產不是我們代謝的核心—我們的心臟代謝焦點。所以我認為那裡有足夠的彈藥來進行額外的交易。

Keay Nakae, Chardan.

凱·中江，查丹。

Congrats on the deal. Just looking for some further clarification about the plans for lung. I think you said you're still taking ARO-RAGE into a Phase 2, maybe first half of next year. But will you look to partner that? And then beyond that, will you look to pursue any other long targets?

恭喜達成交易。只是尋找有關肺部計劃的進一步說明。我想你說過你仍在將 ARO-RAGE 納入第二階段，也許是明年上半年。但你會尋求合作嗎？除此之外，您還會追求其他長期目標嗎？

Sure. Look, yes, I think that ultimately, RAGE should be partnered. That's going to require large and relatively complicated asthma studies, maybe COPD. With our renewed focus on cardiometabolic, it would make sense for us to find the right partner for that. We don't have to do it tomorrow. But at some point, it would make some sense to partner that.

當然。聽著，是的，我認為最終應該與 RAGE 合作。這將需要大量且相對複雜的氣喘研究，也許是慢性阻塞性肺病。隨著我們重新關注心臟代謝，我們有必要為此找到合適的合作夥伴。我們明天不必這樣做。但在某些時候，合作是有意義的。

It could be that it makes sense for us to do a bit more work, some kind of Phase 2 study -- we'll see -- in order to increase the value of a partnership. We haven't made those decisions yet. I'm just telling you what's on the table, I guess.

對我們來說，做更多的工作、某種第二階段的研究——我們將會看到——以增加合作關係的價值可能是有意義的。我們還沒有做出這些決定。我想我只是告訴你桌面上的內容。

Look, we like the pulmonary platform. I think there's an awful lot we can do there, particularly in deep lung targets. And so my hope is that we continue to develop that. Again, less for ourselves -- longer term, at least, less for ourselves and more for partners. It doesn't mean that we wouldn't initiate some programs, but it would mean that we'll be doing those largely on spec. My hope is that we can find partners, who are interested in helping us develop the right medicines against the right targets in pulmonary.

看，我們喜歡肺平台。我認為我們可以在那裡做很多事情，特別是在深部肺部目標方面。所以我希望我們能夠繼續發展這一點。再說一遍，對我們自己來說更少——至少從長遠來看，對我們自己來說更少，對伴侶來說更多。這並不意味著我們不會啟動一些計劃，但這意味著我們將主要按照規範進行這些計劃。我希望我們能找到有興趣幫助我們開發針對肺部正確標靶的正確藥物的合作夥伴。

Brendan Smith, TD Cowen.

布倫丹·史密斯，TD·考恩。

Hi guys. Thanks for taking the questions. Another big congrats from me on the deal. I guess backing really on that last question, just on the pulmonary vertical, have you filled the inbound at this point, or are you in any active discussions about potentially partnering that platform more broadly?

嗨，大家好。感謝您提出問題。我對這筆交易再次表示熱烈祝賀。我想真正支持最後一個問題，只是在肺部垂直方向上，您此時是否已經填滿了入站，或者您是否正在積極討論可能更廣泛地與該平台合作？

I guess, obviously, you already kind of lead there, but to your point, there seems to be a lot of optionality for that across the board. So just wondering where you guys are -- where your head is at on that a little bit more broadly.

我想，顯然，你已經在這方面處於領先地位，但就你的觀點而言，似乎有很多全面的選擇。所以只是想知道你們在哪裡——更廣泛地說，你們的想法在哪裡。

And then can you just maybe confirm for plozasiran if now this renewed focus on cardiometabolic -- does this mean that a commercialization partner is just kind of off the table altogether now and you think you should be able to fully commercialize it across the different segments on your own? Or is that still maybe something you consider like post-SHTG data before the CVOT read out? Thanks.

然後，您是否可以確認 plozasiran 是否現在重新關注心臟代謝——這是否意味著商業化合作夥伴現在完全不存在了，您認為您應該能夠在不同領域將其完全商業化您自己的？或者您仍然認為這類似於 CVOT 讀出之前的 SHTG 後數據？謝謝。

Yes. So we would certainly consider ex-US partners, partner or partners. Within the US, we really see ourselves building out our commercial infrastructure largely around plozasiran and then using that infrastructure to commercialize other cardiometabolic assets as well. But sure, we would certainly consider some ex-US partnership if the right one came around.

是的。因此，我們肯定會考慮前美國合作夥伴、合作夥伴或合作夥伴。在美國，我們確實主要圍繞 plozasiran 來建造我們的商業基礎設施，然後利用該基礎設施將其他心臟代謝資產商業化。但可以肯定的是，如果有合適的合作夥伴出現，我們肯定會考慮與美國以外的國家建立合作關係。

Again, back to lung, we have spoken with folks about lung, as you can imagine. I don't have any guidance on when we may get a pulmonary deal done. As I mentioned, the Sarepta deal is important for us, and it allows us to have some breathing room here. And so I don't expect a pulmonary partnership in the very, very near term, but it's certainly something that we have spoken with other companies about, and we will continue to do that.

再次回到肺部，正如您可以想像的那樣，我們已經與人們談論了肺部。對於我們何時可以完成肺部交易，我沒有任何指導。正如我所提到的，Sarepta 交易對我們來說很重要，它讓我們有一些喘息的空間。因此，我預計短期內不會建立肺部合作關係，但這肯定是我們與其他公司討論過的事情，我們將繼續這樣做。

Mani Foroohar, Leerink.

瑪尼·福魯哈爾，李林克。

Thank you, guys. You have Ryan on for Mani. I'll add my congrats on the deal, and thanks for taking our questions. So maybe first, just a follow-up on a prior question around paying down debt through the BD cash flow from Sarepta and other agreements. Does that mean you plan to utilize this new cash to cover the interest expense on the debt, or are you planning to actively pay down the principal? And if the latter, to what degree and on what time horizon should we expect that?

謝謝你們，夥計們。你讓瑞安代替馬尼。我要對這筆交易表示祝賀，並感謝您提出我們的問題。因此，也許首先，只是對先前關於透過 Sarepta 和其他協議的 BD 現金流償還債務的問題進行跟進。這是否意味著您計劃利用這筆新現金來支付債務利息費用，或者您計劃積極償還本金？如果是後者，我們應該在多大程度上、在什麼時間範圍內期待這種情況？

And then real quick, maybe just circling back to the $300 million near-term milestone for DM1 enrollment, any specifics you guys can provide on the $100 million and $200 million milestones and how those are achieved?

然後很快，也許只是回到 DM1 註冊的 3 億美元近期里程碑，你們能提供有關 1 億美元和 2 億美元里程碑的任何具體資訊以及如何實現這些目標嗎？

Yeah. And so I can't get too granular on that, but I can tell you that it has to do, as you mentioned, with the DM1 program. And it just has to do with when a certain number of patients have been dosed within some of the early cohorts.

是的。因此，我無法對此進行詳細說明，但我可以告訴您，正如您所提到的，它與 DM1 程式有關。這僅僅與一些早期隊列中一定數量的患者接受給藥的時間有關。

We are on track, I believe, to reach that over the first three or so quarters of 2025. Look, that can change as those studies go on, but at least right now, that is our hope. That's our expectation. Regarding the debt, we'll be paying down both interest and principal over time as cash comes in through Sarepta as well as through other partnerships.

我相信，我們預計在 2025 年的前三個季度左右實現這一目標。這是我們的期望。關於債務，隨著時間的推移，我們將透過 Sarepta 以及其他合作夥伴獲得現金，同時償還利息和本金。

William Pickering, Bernstein.

威廉‧皮克林，伯恩斯坦。

Hi. Thank you for taking my question and congrats on the deal. You made some reference to cardiomyocyte targets during the prepared remarks, and I was wondering if you could expand on what sorts of indications you're interested in here, whether it's rare or higher prevalence? Is there a clear demarcation between the cardio targets that you want to pursue independently versus what Sarepta has dibs on? Thank you.

你好。感謝您回答我的問題並祝賀這筆交易。您在準備好的演講中提到了心肌細胞靶標，我想知道您是否可以詳細說明您在這裡感興趣的適應症類型，無論是罕見還是患病率較高？您想要獨立追求的有氧運動目標與 Sarepta 有權實現的目標之間是否有明確的界線？謝謝。

Yeah. So I can't give you too much guidance; I can't give you any guidance, frankly, on what targets we are considering within cardiomyocytes. That's still pretty early. Our non-clinical data have been compelling. And so we view that as a platform that we can start to really consider bringing into the clinic. I can tell you, Sarepta has not given us any targets yet within cardiomyocytes.

是的。所以我不能給你太多指導；坦白說，我無法就我們在心肌細胞內考慮的目標提供任何指導。那還很早。我們的非臨床數據令人信服。因此，我們認為這是一個我們可以開始真正考慮將其引入診所的平台。我可以告訴你，Sarepta 還沒有給我們心肌細胞內的任何目標。

I don't know if they have any, in particular, that they're thinking about right now. They just have the ability to designate some targets within cardiomyocytes as well as skeletal muscle and CNS. So I don't know where they're going to go or when they're going to do that.

我不知道他們現在是否有特別的想法。他們只是有能力指定心肌細胞以及骨骼肌和中樞神經系統內的一些目標。所以我不知道他們要去哪裡或什麼時候這麼做。

We have some ideas on targets. And so my expectation will be that probably sometime in 2025, you might hear a bit more about that.

我們對目標有一些想法。因此，我的期望是，可能在 2025 年的某個時候，您可能會聽到更多相關資訊。

Maya Mamtani, B. Riley.

瑪雅‧馬姆塔尼 (Maya Mamtani)，B. 萊利 (B. Riley)。

Thanks for taking my follow-up. Could you also touch on how your TfR ligand-based targeted approach is different than maybe the other main shuttle approach is being looked at? And what are the attributes you feel allow you to optimally target MAPT? There's a couple of approaches being looked at there. And thanks for taking our follow-up question.

感謝您接受我的跟進。您能否談談您的基於 TfR 配體的靶向方法與正在研究的其他主要穿梭方法有何不同？您認為哪些屬性可以讓您以最佳方式瞄準 MAPT？那裡正在研究幾種方法。感謝您提出我們的後續問題。

Yeah, sure. So we haven't disclosed a lot of details on that. I would refer you to the webinar that we gave a few months ago in October where we covered the CNS platforms and talked a little bit more about that specific platform and how it differentiates itself.

是的，當然。所以我們還沒有透露很多細節。我建議您參考我們幾個月前 10 月舉辦的網路研討會，其中我們介紹了 CNS 平台，並詳細討論了該特定平台及其如何脫穎而出。

And I think structurally, we said it was TfR targeted, but we didn't describe the structure any more specifically than that.

我認為從結構上講，我們說它是針對 TfR 的，但我們沒有比這更具體地描述該結構。

Thank you. And as there are no further questions at this time, i would now like to turn it back over to Chris Anzalone for closing remarks.

謝謝。由於目前沒有其他問題，我現在想將其轉回 Chris Anzalone 進行結束語。

Thanks very much, everyone, for joining us today. This has been an important day for us with this Sarepta deal. We're excited about what that's done for us as a company. We're excited about working with Sarepta. So thanks for joining on the call today, and I wish you all a happy Thanksgiving.

非常感謝大家今天加入我們。對於我們與 Sarepta 的交易來說，今天是重要的一天。我們對這為我們公司所做的一切感到興奮。我們很高興與 Sarepta 合作。感謝您今天參加電話會議，祝大家感恩節快樂。

Thank you for your participation in today's conference. This does include the program. You may now disconnect everyone. Have a great day.

感謝您參加今天的會議。這確實包括該程序。您現在可以斷開所有人的連線。祝你有美好的一天。