Arrowhead Pharmaceuticals Inc (ARWR) 2024 Q3 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。 （操作員說明）

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

我現在將電話會議交給 Arrowhead 投資者關係副總裁 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 2024 third quarter ended June 30, 2024.

謝謝。大家下午好。感謝您今天加入我們，討論 Arrowhead 截至 2024 年 6 月 30 日的 2024 財年第三季業績。

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 commercial activities; and Ken Myszkowski, Chief Financial Officer, who will give a review of the financials. Dr. James Hamilton, Chief of Discovery and Translational Medicine; and Patrick O'Brien, COO and General Counsel, will also be available during the Q&A portion of the call.

今天與我們一起出席的管理層包括總裁兼首席執行官 Chris Anzalone 博士，他將概述本季的情況；臨時首席醫學科學家 Bruce Given 博士將提供我們心臟代謝產品線的最新信息，高級副總裁兼全球心臟代謝特許經營負責人 Andy Davis 將提供商業活動的最新信息；財務長 Ken Myszkowski 將對財務狀況進行審查。 James Hamilton 博士，發現與轉化醫學主管；首席營運長兼總法律顧問 Patrick O'Brien 也將出席電話會議的問答部分。

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. Arrowhead has spent a substantial amount of time building a scalable platform on which a large number of diverse and innovative new medicines have been and will continue to be built. This is the basis of our 20 and 25 initiative where we expect to grow our pipeline to at least 20 clinical stage or marketed products by next year.

謝謝，文斯。大家下午好，感謝您今天加入我們。 Arrowhead 花費了大量時間來建立一個可擴展的平台，在該平台上已經並將繼續建立大量多樣化的創新藥物。這是我們 20 和 25 計畫的基礎，我們預計到明年我們的產品線將增加到至少 20 個臨床階段或上市產品。

Think about what that means for any company, much less one of our size. This initiative represents our commitment to reduce the overall risk profile of the company while expanding our upside potential, and this is important for our long-term value creation.

想想這對任何一家公司意味著什麼，更不用說像我們這樣規模的公司了。這項措施代表了我們致力於降低公司整體風險狀況，同時擴大我們的上行潛力，這對我們的長期價值創造非常重要。

In the short term, however, we need to balance our platform development work with intense focus on bringing our first wholly owned drug candidate to market as quickly and efficiently as possible. We expect that candidate will be plozasiran, and we expect the initial launch to be next year if approved for use in familial chylomicronemia syndrome or FCS. We're working hard to ensure that plozasiran moves rapidly through regulatory NDA and MAA filings for FCS, while executing Phase III clinical studies for SHTG, the second potential indication in our cardiovascular outcomes trial, or CVOT, for mixed hyperlipidemia, the third potential indication. We believe that plozasiran represents a pipeline within a single drug, given the multiple patient populations we can address with it. Bruce will talk about the progress in this program in a moment.

然而，從短期來看，我們需要平衡我們的平台開發工作，並專注於盡快有效地將我們的第一個全資候選藥物推向市場。我們預計該候選藥物將是 plozasiran，如果被批准用於家族性乳糜微粒血症症候群或 FCS，我們預計將於明年首次推出。我們正在努力確保plozasiran 快速通過FCS 監管NDA 和MAA 備案，同時執行SHTG（我們心血管結果試驗中的第二個潛在適應症）的III 期臨床研究，或CVOT（混合型高脂血症）（第三個潛在適應症） 。考慮到我們可以用 plozasiran 治療多種患者群體，我們相信 plozasiran 代表了單一藥物的管道。 Bruce 稍後會談到這個計劃的進展。

We are currently building out our commercial infrastructure to enable an initial launch in 2025 and then scale to support progressively larger patient populations over the coming years. Andy will talk about where we are with this process in a moment.

我們目前正在建造商業基礎設施，以便在 2025 年首次推出，然後在未來幾年擴大規模以支持逐漸擴大的患者群體。安迪稍後將討論我們在這個過程中的進展。

On September 1, 1987, the first statin was approved by the FDA. This event changed the world because it ushered in an era during which physicians would appreciate the risks associated with high LDL cholesterol and importantly would have the tools to lower it. It feels to us like we are at a similar point with triglycerides with a few notable differences.

1987年9月1日，第一個他汀類藥物獲得FDA核准。這一事件改變了世界，因為它開創了一個時代，在這個時代裡，醫生會認識到高低密度脂蛋白膽固醇的相關風險，重要的是會擁有降低它的工具。我們感覺到三酸甘油酯處於相似的階段，但有一些顯著的差異。

First, we have the luxury of being able to grow our way into a large market. We expect to begin commercializing plozasiran in the small FCS market then grow into the large SHTG market around 2027 and ultimately serve the very large mixed hyperlipidemia market after CVOT is complete.

首先，我們有幸能夠進入一個大市場。我們預計將在小型 FCS 市場開始商業化 plozasiran，然後在 2027 年左右發展到大型 SHTG 市場，並最終在 CVOT 完成後服務於非常大的混合高脂血症市場。

Second, we feel like we are virtually alone in our ability to drastically lower triglycerides and therefore serve these markets appropriately. While there have been 8 FDA-approved statins to compete to lower LDL, our data suggests to us that there is simply no other near-term therapies that can match plozasiran's activity.

其次，我們覺得我們實際上是唯一有能力大幅降低三酸甘油酯並因此適當服務這些市場的公司。雖然 FDA 批准了 8 種他汀類藥物來競爭降低 LDL，但我們的數據表明，根本沒有其他近期療法可以與 plozasiran 的活性相符。

If triglycerides or bad actors, wouldn't patients and physicians want to lower them as much as possible? We believe they will. This is a big commercial opportunity, and we believe Arrowhead has the most promising medicine that is poised to make a big impact over the coming years.

如果三酸甘油酯或不良行為者，患者和醫生難道不想盡可能降低它們嗎？我們相信他們會的。這是一個巨大的商業機會，我們相信 Arrowhead 擁有最有前途的藥物，預計將在未來幾年產生巨大影響。

Before discussing other progress we've made recently, I want to talk about the announcement we made this afternoon. I think it's clear that we have dramatic upside opportunities in plozasiran in the near term and in multiple other programs over the medium and long term. What was less clear to investors was how we would finance these development programs until we get to a point where commercial revenue becomes a significant source of capital and ultimately brings us to cash flow positive position.

在討論我們最近的其他進展之前，我想談談我們今天下午發布的公告。我認為很明顯，我們在 plozasiran 的短期內以及在中長期的多個其他項目中都擁有巨大的上昇機會。投資者不太清楚的是，我們將如何為這些開發項目提供資金，直到商業收入成為重要的資本來源並最終使我們的現金流達到正值。

To that end, today, we announced a transaction with Sixth Street that provides an immediate and meaningful strengthening of our balance sheet with long-term, low-cost, non-dilutive capital to fund innovative -- I'm sorry, to fund innovation and growth opportunities across Arrowhead's pipeline. The $500 million senior secured credit facility includes $400 million funded at close, with an additional $100 million available at Arrowhead's option, subject to mutual agreement between Sixth Street and Arrowhead during the 7-year term of the agreement. This is debt, but the risk-sharing structure is very attractive to us. There are no scheduled amortization payments during this term and no scheduled cash pay coupon interest payments.

為此，今天，我們宣布了與第六街的一項交易，該交易透過長期、低成本、非稀釋性資本為創新提供資金，從而立即有效地強化我們的資產負債表——對不起，為創新提供資金以及 Arrowhead 管道中的成長機會。 5 億美元的優先擔保信貸額度包括結束時融資的 4 億美元，以及 Arrowhead 可選擇額外提供的 1 億美元，具體取決於 Sixth Street 和 Arrowhead 在 7 年協議期限內雙方達成的協議。這是債務，但風險分擔結構對我們來說非常有吸引力。在此期間沒有計劃攤銷付款，也沒有計劃現金支付息票利息支付。

In addition, it has an attractive 7-year term during which we hope to be building our commercial revenue substantially. It has other risk-sharing characteristics where payments are to be made to partially repay loans under the credit facility with a portion of the proceeds from certain transactions such as future inflows from partnerships and collaborations and commercial revenue.

此外，它的 7 年期限很有吸引力，我們希望在此期間大幅增加我們的商業收入。它具有其他風險分擔特徵，即以某些交易的部分收益（例如夥伴關係和合作的未來流入以及商業收入）來部分償還信貸安排下的貸款。

So we don't really have cash outflow obligations unless we have cash inflows from other sources. This deal makes a lot of sense for us and the great team at Sixth Street has been creative in building a custom structured product that is appropriate for Arrowhead. This growth capital comes at a perfect time.

因此，除非我們有來自其他來源的現金流入，否則我們實際上沒有現金流出義務。這筆交易對我們來說意義重大，第六街的優秀團隊一直創造性地建造了適合 Arrowhead 的客製化結構化產品。這種成長資本來得正是時候。

During the quarter, we also announced a $50 million milestone payment that we received from Royalty Pharma following the completion of enrollment of the Phase 3 OCEAN-a Outcomes Trial of olpasiran, being conducted by Amgen. These are important steps to build our balance sheet but not the last. We view our capital needs through the lens of plozasiran development and see the potential for significant revenues coming out of the SHTG market.

在本季度，我們還宣布了在安進 (Amgen) 進行的 olpasiran 3 期 OCEAN-a 結果試驗完成入組後，我們從royalty Pharma 收到了 5000 萬美元的里程碑付款。這些是建立我們的資產負債表的重要步驟，但不是最後一步。我們從 plozasiran 開發的角度審視我們的資本需求，並看到 SHTG 市場帶來大量收入的潛力。

As such, we want to ensure that we have a financial bridge to that market, which we believe we could launch into in 2027. We have many tools to fund operations over those 3 years, including potential milestone payments from our existing four partnerships, new partnerships and license agreements, possible financing and return for caps royalties on plozasiran sales and revenue from commercializing into the FCS market, which we expect to begin next year.

因此，我們希望確保我們擁有通往該市場的財務橋樑，我們相信我們可以在2027 年進入該市場。的潛在里程碑付款、新的合作夥伴關係和許可協議、可能的融資和 plozasiran 銷售上限特許權使用費的回報以及 FCS 市場商業化的收入，我們預計將於明年開始。

Before turning the call over to Bruce to discuss the plozasiran clinical programs and data, I want to review a few other key accomplishments from the recent period. First, we announced top line results from the pivotal Phase 3 PALISADE study of plozasiran in patients with FCS. The study met its primary endpoint in all key secondary endpoints. We see these data as best-in-class. This is Arrowhead's first therapy to show clinical efficacy in a Phase 3 study, which represents validation of all the hard work from so many talented Arrowhead employees, our collaborators and the FCS community over the years.

在將電話轉給 Bruce 討論 plozasiran 臨床計畫和數據之前，我想回顧一下最近一段時間的其他一些關鍵成就。首先，我們發表了 plozasiran 在 FCS 患者中的關鍵 3 期 PALISADE 研究的主要結果。該研究在所有關鍵次要終點中均達到了主要終點。我們認為這些數據是同類最佳的。這是 Arrowhead 的第一個在 3 期研究中顯示出臨床療效的療法，這代表了多年來許多才華橫溢的 Arrowhead 員工、我們的合作者和 FCS 社區的所有辛勤工作的驗證。

Also during the quarter, we presented new interim clinical data on ARO-RAGE, our investigational RNAi-based medicine for the treatment of inflammatory lung diseases, such as asthma at the American Thoracic Society 2024 International Conference. These were important data as they represent not only translation of preclinical data to clinical data in normal healthy volunteers but also to an asthma patient population. We are currently working on the design of a Phase 2 study of ARO-RAGE.

同樣在本季度，我們在美國胸腔科學會 2024 年國際會議上展示了 ARO-RAGE 的新中期臨床數據，ARO-RAGE 是我們基於 RNAi 的研究藥物，用於治療哮喘等發炎性肺部疾病。這些都是重要的數據，因為它們不僅代表了正常健康志願者的臨床前數據到臨床數據的轉化，而且還代表了氣喘患者群體的臨床前數據的轉化。我們目前正在設計 ARO-RAGE 的第二期研究。

Turning to the earlier side of our pipeline, we presented preclinical data on ARO-INHBE at the American Diabetes Association, or ADA, 84th Scientific Sessions. INHBE is an investigational RNAi-based medicine that we are studying for the treatment of obesity and metabolic diseases. In pharmacological studies in obese and diabetic mouse models, INHBE-siRNA administration resulted in multiple promising findings, including the following, 95% reduction in INHBE/mRNA expression, 19% suppression of body weight compared to saline controls, 26% loss of fat mass and importantly, preservation of lean mass.

轉向我們管道的早期部分，我們在美國糖尿病協會 (ADA) 第 84 屆科學會議上展示了 ARO-INHBE 的臨床前數據。 INHBE 是一種基於 RNAi 的研究藥物，我們正在研究它用於治療肥胖和代謝疾病。在肥胖和糖尿病小鼠模型的藥理學研究中，INHBE-siRNA 給藥產生了多項有希望的發現，包括：與鹽水對照相比，INHBE/mRNA 表達降低95%，體重抑制19%，脂肪量減少26%重要的是，維持瘦體重。

Our preclinical data presented at ADA suggests that INHBE reduction with siRNA is a promising new approach to address obesity and metabolic diseases, and we think support advancing ARO-INHBE into clinical trials. We'll be discussing these data and also announcing a new program that directly targets adipose tissue next week at our R&D webinar on obesity and metabolic diseases. These are exciting additions indeed to our cardiometabolic franchise.

我們在 ADA 上提交的臨床前數據表明，用 siRNA 減少 INHBE 是解決肥胖和代謝疾病的一種有前景的新方法，我們認為支持將 ARO-INHBE 推進臨床試驗。我們將在下週關於肥胖和代謝疾病的研發網路研討會上討論這些數據，並宣布一項直接針對脂肪組織的新計畫。這些確實是我們心臟代謝系列產品令人興奮的補充。

Please note the new date of this event is August 14. It was originally planned for August 15, but the date was changed to accommodate the schedule of an external speaker who will be joining us. So be sure to listen in as these early-stage programs in our cardiometabolic pipeline are particularly interesting and fit well with our growing development and commercial presence in the space.

請注意，該活動的新日期為 8 月 14 日。因此，請務必傾聽，因為我們心臟代謝管道中的這些早期項目特別有趣，並且非常適合我們在該領域不斷發展的發展和商業存在。

Lastly, since we have so much going on in our broad pipeline, during the quarter we launched the 2024 summer series of R&D webinars to highlight some of our work. Each month starting May and ending in September, we highlight different therapeutic areas and programs in our pipeline. We have now completed webinars on our muscle programs, our late-stage cardiometabolic programs and our pulmonary programs. As I mentioned, next week, on August 14, we will cover our obesity and metabolic programs. And in September, we will cover our CNS programs, including updates on the delivery platforms and on undisclosed candidates planned to enter clinical development this year. Clearly, there's a lot going on and a lot to be excited about at Arrowhead.

最後，由於我們在廣泛的管道中發生了很多事情，因此在本季度我們推出了 2024 年夏季系列研發網路研討會，以重點介紹我們的一些工作。從五月開始到九月結束的每個月，我們都會重點介紹我們管道中的不同治療領域和計畫。我們現已完成有關肌肉計劃、後期心臟代謝計劃和肺部計劃的網路研討會。正如我所提到的，下週，即 8 月 14 日，我們將報告我們的肥胖和代謝計劃。 9 月，我們將報告我們的 CNS 項目，包括交付平台的更新以及計劃今年進入臨床開發的未公開候選藥物的更新。顯然，Arrowhead 正在發生很多事情，也有很多令人興奮的事情。

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

有了這個概述，我現在想把電話轉給布魯斯。布魯斯？

Thank you, Chris. Good afternoon, everyone. We've been very impressed with the clinical data generated with plozasiran in each patient population we've studied. And we believe it is best in class across the board.

謝謝你，克里斯。大家下午好。我們對我們研究的每個患者群體中使用 plozasiran 產生的臨床數據印象深刻。我們相信它是同類產品中最好的。

Starting in healthy volunteers and moving to patients with mixed hyperlipidemia and severe hypertriglyceridemia or SHTG, and on to patients with genetically or clinically diagnosed FCS, we have seen very consistent high levels of target engagement and downstream changes to lipids and lipoproteins. This makes sense and was our expectation, but it's still gratifying to see data meet or exceed expectations.

從健康志願者開始，到混合性高血脂症和嚴重高三酸甘油酯血症或SHTG 患者，再到基因或臨床診斷的FCS 患者，我們看到了非常一致的高水平靶點參與以及脂質和脂蛋白的下游變化。這是有道理的，也是我們的預期，但看到數據達到或超出預期仍然令人欣慰。

To review, Apolipoprotein C-III or APOC3 is the gene target for plozasiran. It is a component of triglyceride-rich lipoproteins, or TRLs, and a known regulator of triglyceride metabolism. APOC3 inhibits the breakdown of TRLs by lipoprotein lipase and inhibits uptake of remnant cholesterols in the liver. The goal of treatment of plozasiran is to reduce the level of APOC3, thereby reducing triglycerides and restoring lipids to more normal levels.

回顧一下，載脂蛋白 C-III 或 APOC3 是 plozasiran 的基因標靶。它是富含三酸甘油酯的脂蛋白 (TRL) 的組成部分，也是已知的三酸甘油酯代謝調節劑。 APOC3 抑制脂蛋白脂肪酶對 TRL 的分解，並抑制肝臟對殘餘膽固醇的吸收。 plozasiran 的治療目標是降低 APOC3 水平，從而降低三酸甘油酯並將血脂恢復到更正常的水平。

Over the past few months, we have been presented -- we have presented and published Phase 2 data on plozasiran in patients with mixed hyperlipidemia in the MUIR study and in patients with SHTG in the SHASTA-2 study. We have also reported top line results from the PALISADE Phase 3 study in patients with FCS.

在過去的幾個月裡，我們在 MUIR 研究中提出並發表了 plozasiran 在混合性高脂血症患者中的 2 期數據，以及在 SHASTA-2 研究中在 SHTG 患者中的 2 期數據。我們也報告了針對 FCS 患者的 PALISADE 3 期研究的主要結果。

I want to spend a moment going over the highlights from these studies. Starting with mixed hyperlipidemia in the MUIR study, treatment with plozasiran in mixed hyperlipidemia achieved reductions in triglyceride rich lipoproteins, a genetically validated target associated with increased risk of atherosclerotic cardiovascular disease. These data were presented in an oral presentation at the European Atherosclerosis Society, 92nd Congress and simultaneously published in the New England Journal of Medicine.

我想花點時間回顧這些研究的要點。從MUIR 研究中的混合性高脂血症開始，使用plozasiran 治療混合性高脂血症可降低富含三酸甘油酯的脂蛋白，這是一個經過基因驗證的目標，與動脈粥樣硬化性心血管疾病風險增加相關。這些數據在歐洲動脈粥狀硬化學會第 92 屆大會上以口頭報告形式提出，同時發表在《新英格蘭醫學雜誌》。

At week 24, representing trough effect after two quarterly doses, plozasiran treatment was associated with placebo-adjusted reductions in triglycerides of up to minus 62%. Fasting triglyceride levels were normalized, which means patients achieved levels below 150 milligrams per deciliter in 79% to 92% of patients randomized to a treatment arm.

在第 24 週，即兩個季度劑量後的谷值效應，plozasiran 治療與安慰劑調整後的三酸甘油酯降低高達 -62% 相關。空腹三酸甘油酯水平正常化，這意味著在隨機接受治療組的患者中，79% 至 92% 的患者達到了低於 150 毫克/分升的水平。

Commensurate reductions in APOC3 of up to 79% were observed with strong positive correlations with changes in triglyceride levels. There were other important changes in other atherogenic lipoprotein parameters, including non-HDL-C, apolipoprotein B and remnant cholesterol, with strong correlations with the reductions in triglyceride levels.

觀察到 APOC3 相應減少高達 79%，與三酸甘油酯水平的變化呈強正相關。其他致動脈粥樣硬化脂蛋白參數也存在其他重要變化，包括非 HDL-C、載脂蛋白 B 和殘餘膽固醇，與三酸甘油酯水平的降低密切相關。

Plozasiran demonstrated a favorable safety profile in the MUIR study. The overall rates of occurrence of treatment emergent adverse events and discontinuations were similar for plozasiran and placebo throughout the 48 weeks of observation.

Plozasiran 在 MUIR 研究中表現出良好的安全性。在整個 48 週的觀察期間，plozasiran 和安慰劑的治療緊急不良事件和中斷的總體發生率相似。

Mixed hyperlipidemia also called mixed dyslipidemia is a highly prevalent disorder characterized by elevated LDL cholesterol and triglyceride levels. Despite the efficacy of LDL-lowering therapies and reducing atherosclerotic cardiovascular disease in mixed hyperlipidemia, there remains substantial residual risk attributed to elevated non-HDL cholesterol, driven by remnant cholesterol and triglyceride-rich lipoproteins. Genome-wide association and Mendelian randomization studies also support a causal role for triglyceride-rich lipoproteins in atherosclerotic cardiovascular disease.

混合性高血脂症也稱為混合性血脂異常，是一種非常普遍的疾病，其特徵是低密度脂蛋白膽固醇和三酸甘油酯水平升高。儘管降低LDL 療法和減少混合性高脂血症中的動脈粥樣硬化性心血管疾病有效，但由於殘餘膽固醇和富含三酸甘油酯的脂蛋白驅動的非HDL 膽固醇升高，仍然存在很大的殘餘風險。全基因組關聯和孟德爾隨機化研究也支持富含三酸甘油酯的脂蛋白在動脈粥狀硬化性心血管疾病中的因果關係。

Based on the promising results from the MUIR study, we are now gearing up to initiate the Phase 3 CAPITAN cardiovascular outcomes trial, which is designed to enroll patients with mixed hyperlipidemia and who have had or are a risk for a cardiovascular event.

基於 MUIR 研究的令人鼓舞的結果，我們現在正準備啟動 3 期 CAPITAN 心血管結局試驗，該試驗旨在招募患有混合性高脂血症以及已經發生或有心血管事件風險的患者。

Moving on to the SHTG population, there are patients with much higher triglyceride levels than generally seen in the mixed hyperlipidemia population. For SHTG, we presented data from the SHASTA-2 study at the American College of Cardiology Meeting this spring and simultaneously published the results in the journal JAMA Cardiology.

再看 SHTG 族群，有些患者的三酸甘油酯水平比混合性高脂血症人群中通常看到的要高得多。對於 SHTG，我們在今年春天的美國心臟病學會會議上展示了 SHASTA-2 研究的數據，並同時在《JAMA Cardiology》雜誌上發表了結果。

In SHASTA-2, treatment with plozasiran led to dose-dependent placebo-adjusted reductions in week 24 in triglycerides of up to minus 57%, driven by reductions in APOC3 of up to minus 77%. Mean maximum non-placebo adjusted reductions from baseline and triglycerides in APOC3 were up to minus 86% and minus 90%, respectively, and typically occurred around week 16 or week 20.

在 SHASTA-2 中，plozasiran 治療導致第 24 週三酸甘油酯劑量依賴性安慰劑調整降低高達 -57%，這是由 APOC3 降低高達 -77% 驅動的。 APOC3 中三酸甘油酯相對於基線和三酸甘油酯的平均最大非安慰劑調整降低分別高達 -86% 和 -90%，通常發生在第 16 週或第 20 週左右。

Among subjects treated with plozasiran, at the week 24 trough time point, greater than 90% achieved -- receiving the 25 or 50 milligram doses achieved triglycerides less than 500 milligrams per deciliter, an important threshold associated with increased risk of acute pancreatitis.

在接受plozasiran 治療的受試者中，在第24 週的谷時間點，超過90% 的受試者達到了目標——接受25 或50 毫克劑量的三酸甘油酯達到了低於500 毫克/分升，這是與急性胰臟炎風險增加相關的重要閾值。

In addition, around half of the subjects of these doses achieved normal triglyceride levels of less than 150 milligrams at week 24, which is surprising given the mean high starting levels of almost 900 mgs per deciliter.

此外，大約一半接受這些劑量的受試者在第24 週時達到了低於150 毫克的正常三酸甘油酯水平，考慮到平均高起始水平幾乎為每分升900 毫克，這是令人驚訝的。

In addition to reduction in triglycerides, subjects treated plozasiran also showed improvements in multiple atherogenic lipid and lipoprotein levels, including remnant cholesterol, HDL cholesterol and non-HDL cholesterol.

除了三酸甘油酯降低外，接受 plozasiran 治療的受試者還表現出多種致動脈粥樣硬化脂質和脂蛋白水平的改善，包括殘餘膽固醇、高密度脂蛋白膽固醇和非高密度脂蛋白膽固醇。

Plozasiran demonstrated a favorable safety profile at SHASTA-2, observed adverse events generally reflected the comorbidities and underlying conditions of the study population. SHTG is characterized by triglyceride levels greater than 500 mgs per deciliter and is known to significantly increase the risk of atherosclerotic cardiovascular disease and acute pancreatitis, which can occur with recurrent attacks requiring repeat hospitalization admissions and worsening outcomes.

Plozasiran 在 SHASTA-2 中表現出良好的安全性，觀察到的不良事件通常反映了研究族群的合併症和潛在狀況。 SHTG 的特徵是三酸甘油酯水平高於500 毫克/分升，已知會顯著增加動脈粥狀硬化性心血管疾病和急性胰臟炎的風險，這些疾病可能會因反覆發作而發生，需要重複住院並導致結局惡化。

Pancreatic risk increases as triglyceride levels increase. Currently available drug therapies generally don't sustainably reduce triglycerides below the pancreatitis risk threshold in this patient population. Based on the promising SHASTA-2 data, we have initiated and started dosing in both the SHASTA-3 and SHASTA-4 Phase 3 studies in patients with SHTG.

隨著三酸甘油酯水平的升高，胰臟風險也會增加。目前可用的藥物療法通常無法持續地將三酸甘油酯降低到該患者族群的胰臟炎風險閾值以下。基於有希望的 SHASTA-2 數據，我們已啟動並開始在 SHTG 患者中進行 SHASTA-3 和 SHASTA-4 3 期研究。

We are also working towards initiating SHASTA-5, a Phase 3 study in patients with SHTG that are at high risk of acute pancreatitis. SHASTA-5 will have a primary endpoint of incidence of new episodes of pancreatitis compared with placebo. We do not see this study as necessary for regulatory approval in SHTG, but we do see it as an important study to potentially show the value of treatment with plozasiran in reducing the risk of acute pancreatitis. If positive, these results should be helpful for all stakeholders, including patients, health care providers and payers.

我們也致力於啟動 SHASTA-5，這是一項針對急性胰臟炎高風險 SHTG 患者的 3 期研究。與安慰劑相比，SHASTA-5 的主要終點是新興胰臟炎的發生率。我們認為這項研究對於 SHTG 的監管批准沒有必要，但我們確實認為它是一項重要的研究，有可能顯示 plozasiran 治療在降低急性胰臟炎風險方面的價值。如果是正面的，這些結果應該對所有利害關係人都有幫助，包括病患、醫療保健提供者和付款人。

Lastly, during the quarter, we gave a top line report on the Phase 3 PALISADE study in patients with genetically confirmed or clinically diagnosed FCS. The strong results from PALISADE significantly build upon the promising results from the Phase 2 SHASTA-2-and MUIR studies. The primary endpoint for the PALISADE study was placebo-adjusted median change in triglycerides in month 10.

最後，在本季度，我們針對基因確診或臨床診斷的 FCS 患者進行了 3 期 PALISADE 研究，提供了一份重要報告。 PALISADE 的強勁結果很大程度上建立在 2 期 SHASTA-2 和 MUIR 研究的有希望的結果的基礎上。 PALISADE 研究的主要終點是第 10 個月時安慰劑調整後三酸甘油酯的中位數變化。

At that time point, patients treated with quarterly doses of 25 and 50 milligrams plozasiran achieved median triglyceride reductions of minus 80% and minus 78%, respectively. About 12 patients treated with 25 and 50 milligrams plozasiran, achieved median triglyceride reductions of minus 78% and minus 73%, respectively. These compared with the median triglyceride reductions of placebo-treated patients of minus 17% in month 10 and minus 7% in month 12. Mean reductions in APOC3 at month 10 were minus 88% and minus 94% at 25 and 50 milligrams plozasiran, respectively. All of these changes were highly significant when comparing plozasiran to placebo.

在該時間點，每季接受 25 毫克和 50 毫克 plozasiran 治療的患者三酸甘油酯中位數分別降低了負 80% 和負 78%。大約 12 名患者接受 25 毫克和 50 毫克 plozasiran 治療，三酸甘油酯中位數分別降低了負 78% 和負 73%。與此相比，安慰劑治療患者的三酸甘油酯中位數下降在第10 個月為負17%，在第12 個月為負7%。 APOC3 的平均下降分別為負88% 和負94% 。當將 plozasiran 與安慰劑進行比較時，所有這些變化都非常顯著。

PALISADE successfully met the primary endpoint in all key secondary endpoints, including reducing the incidence of acute pancreatitis compared to placebo. There were four multiplicity-controlled key secondary endpoints. Percent change for baseline in month 10 to 12 averaged in fasting triglycerides, percent change from baseline in month 10 in fasting APOC3, percent change from baseline in month 12 in fasting APOC3. And finally, incidents of positively adjudicated events of acute pancreatitis during the randomized period.

PALISADE 成功地達到了所有關鍵次要終點的主要終點，包括與安慰劑相比降低了急性胰臟炎的發生率。有四個多重控制的關鍵次要終點。第 10 至 12 個月空腹三酸甘油酯平均基線變化百分比、空腹 APOC3 相對於第 10 個月基線的變化百分比、空腹 APOC3 相對於第 12 個月基線的變化百分比。最後，隨機期間積極判定的急性胰臟炎事件的發生率。

Plozasiran demonstrated a favorable safety profile in the PALISADE study, the number of subjects reporting emergent adverse events were similar in the plozasiran and placebo groups, severe and serious AEs were less common with plozasiran than with placebo. The most common AEs reported were abdominal pain, COVID-19, nasopharyngitis, headache and nausea. This study was accepted as a late-breaker oral presentation at the European Society of Cardiology 2024, coming up on September 2, 2024 in London.

Plozasiran 在PALISADE 研究中表現出良好的安全性，在plozasiran 組和安慰劑組中報告緊急不良事件的受試者數量相似，與安慰劑組相比，plozasiran 組中嚴重和嚴重AE 的發生率較低。最常見的不良事件是腹痛、COVID-19、鼻咽炎、頭痛和噁心。這項研究被接受為 2024 年歐洲心臟學會的最新口頭報告，將於 2024 年 9 月 2 日在倫敦舉行。

Since that's Labor Day in the US, we also plan to have an investor call the following day on September 3, 2020. Dr. Gerald Watts, a principal investigator for PALISADE and the presenter of the data at the European Society of Cardiology, will join the investor call to present the data and discuss the exciting results.

由於當天是美國勞動節，我們還計劃在第二天（即 2020 年 9 月 3 日）召開投資者電話會議。數據並討論令人興奮的結果。

I'll now turn the call over to Andy to give a few remarks on where we are with commercial planning and readiness. Andy?

我現在將把電話轉給安迪，就我們的商業規劃和準備情況發表一些評論。安迪？

Thank you, Bruce. We're on track with our launch preparations for plozasiran in familial chylomicronemia syndrome, or FCS. And let me begin by talking a little bit about our Expanded Access Program, or EAP. We initiated the EAP to ensure patients who roll off our PALISADE trial, maintain access to plozasiran and to make investigational plozasiran available outside of a clinical trial for other patients with FCS who meet certain program eligibility criteria, if requested by their treating physician.

謝謝你，布魯斯。我們正在按計劃進行用於治療家族性乳糜微粒血症綜合症（FCS）的 plozasiran 的上市準備工作。首先讓我談談我們的擴展訪問計劃（EAP）。我們啟動 EAP 是為了確保退出 PALISADE 試驗的患者繼續獲得 plozasiran，並在臨床試驗之外為符合某些計劃資格標準的其他 FCS 患者（如果治療醫生要求）提供研究性 plozasiran。

We've fielded requests for additional information about the EAP from physician societies and treating physicians who may have appropriate FCS patients. And our medical affairs team is already out in the field engaging with these individuals to help them understand the program.

我們已向醫師協會和可能擁有合適 FCS 患者的治療醫師提出請求，要求提供更多有關 EAP 的資訊。我們的醫療事務團隊已經在現場與這些人接觸，幫助他們了解該計劃。

As you know, this would be Arrowhead's first commercial product. So we're building a best-in-class organization that will support the patients who we hope will benefit from plozasiran. This is obviously a big task, but we're up to the challenge.

如你所知，這將是 Arrowhead 的第一個商業產品。因此，我們正在建立一個一流的組織，為我們希望從 plozasiran 受益的患者提供支援。這顯然是一項艱鉅的任務，但我們已經做好迎接挑戰的準備。

The buildout of our medical affairs and commercial infrastructure is right where it needs to be at this time in commercialization. Our entire medical affairs and commercial leadership team is solidly in place, and the team we've assembled has deep experience in the cardiometabolic and lipid therapeutic areas.

我們的醫療事務和商業基礎設施的建設正是目前商業化所需要的。我們的整個醫療事務和商業領導團隊已經穩固到位，我們組建的團隊在心臟代謝和脂質治療領域擁有豐富的經驗。

We've already done extensive mapping of the health care professionals, or HCPs, most likely to treat FCS patients and prescribe plozasiran if approved. Our market research leads us to believe these HCPs have been impressed with the top line results from our PALISADE trial with particular note of the unprecedented triglyceride lowering and statistically significant reduction of acute pancreatitis risk.

我們已經對最有可能治療 FCS 患者並開出 plozasiran（如果獲得批准）的醫療保健專業人員 (HCP) 進行了廣泛的調查。我們的市場研究使我們相信這些 HCP 對 PALISADE 試驗的主要結果印象深刻，特別是三酸甘油酯前所未有的降低以及急性胰臟炎風險統計上顯著的降低。

As Bruce mentioned, plozasiran achieved deep and durable reductions in triglycerides of approximately minus 80% from baseline, demonstrating for the first time the real possibility for FCS patients to lower their triglycerides below important guideline-directed thresholds of acute pancreatitis risk.

正如 Bruce 所提到的，plozasiran 使三酸甘油酯較基線深度持久降低約-80%，首次證明 FCS 患者確實有可能將其三酸甘油酯降低到重要的指南指導的急性胰臟炎風險閾值以下。

Finally, our best-in-class patient and caregiver support program is taking shape. We've selected an exclusive specialty pharmacy and patient hub with expert support for patients with rare conditions and we're presently crafting the finer details of our patient and caregiver support ecosystem to ensure patients can easily start and stay on therapy. I look forward to talking more with you in the future about how we see the commercial market opportunity and how we intend to bring plozasiran to the many patients who could benefit from this new therapy.

最後，我們一流的患者和護理人員支援計劃正在形成。我們選擇了一個獨家的專業藥房和患者中心，為患有罕見疾病的患者提供專家支持，目前我們正在為患者和護理人員支持生態系統制定更詳細的細節，以確保患者可以輕鬆開始並繼續治療。我期待著將來與您更多地討論我們如何看待商業市場機會，以及我們打算如何將 plozasiran 帶給許多可以從這種新療法中受益的患者。

I'll now turn the call over to Ken.

我現在會把電話轉給肯。

Thank you, Andy, and good afternoon, everyone. As we reported today, our net loss for the quarter ended June 30, 2024, was $170.8 million or $1.38 per share based on $124.2 million fully diluted weighted average shares outstanding. This compares with a net loss of $102.9 million or $0.96 per share based on $107 million fully diluted weighted average shares outstanding for the quarter ended June 30, 2023.

謝謝你，安迪，大家下午好。正如我們今天報道的，截至 2024 年 6 月 30 日的季度淨虧損為 1.708 億美元，即每股 1.38 美元，基於 1.242 億美元的完全稀釋加權平均已發行股票計算。相較之下，根據截至 2023 年 6 月 30 日的季度的 1.07 億美元完全稀釋加權平均流通股計算，淨虧損為 1.029 億美元，即每股 0.96 美元。

No revenue was recorded in the quarter ended June 30, 2024. Revenue of $15.8 million was recorded in the quarter ended June 30, 2023. Revenue is recognized as we complete our performance obligations or key developmental milestones are reached. Revenue in the prior period primarily related to the recognition of payments received from our license and collaboration agreement with Takeda.

截至 2024 年 6 月 30 日的季度沒有記錄收入。上一期間的收入主要與確認從我們與武田的許可和合作協議中收到的付款有關。

Total operating expenses for the quarter ended June 30, 2024, were $176.1 million compared to $118.5 million for the quarter ended June 30, 2023. The key drivers of this change were increased research and development costs, primarily discovery and candidate costs as the company's pipeline of discovery candidates has advanced into novel therapeutic areas and tissue types and clinical candidates has increased and progressed into later stages of development.

截至2024 年6 月30 日的季度總營運費用為1.761 億美元，而截至2023 年6 月30 日的季度為1.185 億美元。發現和候選成本的發現候選藥物已進入新的治療領域和組織類型，臨床候選藥物也增加並進入後期開發階段。

Net cash used in operating activities during the quarter ended June 30, 2024, was $115.4 million compared with $21.4 million for the quarter ended June 30, 2023. The increase in cash used in operating activities is driven primarily by higher research and development expenses, as well as lower cash revenue versus the prior year.

截至 2024 年 6 月 30 日的季度營運活動使用的現金淨額為 1.154 億美元，而截至 2023 年 6 月 30 日的季度為 2,140 萬美元。現金收入較上年下降。

Our footprint expansion is mostly complete with final payments to be made over the next several months, totaling about $30 million, after which we expect capital expenditures to be nominal.

我們的足跡擴張已基本完成，最終付款將在未來幾個月內支付，總計約 3000 萬美元，之後我們預計資本支出將是像徵性的。

Turning to our balance sheet. Our cash and investments totaled $436.7 million at June 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, partially offset by ongoing cash burn.

轉向我們的資產負債表。截至2024 年6 月30 日，我們的現金和投資總額為4.367 億美元，而截至2023 年9 月30 日為4.036 億美元。持續的現金消耗所抵消。

Today, we announced a financing agreement with Sixth Street for significant long-term non-dilutive capital. The $500 million senior secured credit facility includes $400 million funded at close and an additional $100 million available at Arrowhead's option, subject to mutual agreement between Sixth Street and Arrowhead.

今天，我們宣布與第六街達成一項融資協議，以獲得大量長期非稀釋資本。 5 億美元的優先擔保信貸額度包括交易結束時提供的 4 億美元以及 Arrowhead 可選擇提供的額外 1 億美元，具體取決於 Sixth Street 和 Arrowhead 之間的共同協議。

Inclusive of the upfront cash from Sixth Street before deducting fees, our pro forma cash balance is approximately $840 million and significantly enhances our liquidity toward our global commercial launch of plozasiran, while also supporting advancement of our late-stage clinical trials and other discovery efforts. Our common shares outstanding at June 30, 2024, were $124.2 million.

包括扣除費用前第六街的預付款在內，我們的預計現金餘額約為8.4 億美元，顯著增強了我們在全球商業推出plozasiran 時的流動性，同時也支持我們後期臨床試驗和其他發現工作的進展。截至 2024 年 6 月 30 日，我們已發行的普通股為 1.242 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. We had a highly productive quarter and feel that all pieces are now in place to begin the transition into a commercial stage company. Completed Phase 3 study in PALISADE that we intend to use to file for regulatory approval to launch plozasiran in patients with FCS. The SUMMIT suite of clinical studies, including PALISADE and the Shasta, MUIR and CAPITAN studies are all underway or at advanced stages and are designed to show the value of plozasiran in multiple patient populations. As I mentioned, we view plozasiran as a pipeline within a single drug, and these studies have the potential of enabling that.

謝謝，肯。我們度過了一個高產的季度，並認為所有部件現在都已就位，可以開始向商業階段的公司過渡。已完成 PALISADE 的 3 期研究，我們打算利用研究申請監管部門批准在 FCS 患者中推出 plozasiran。 SUMMIT 臨床研究套件，包括 PALISADE 和 Shasta、MUIR 和 CAPITAN 研究均正在進行或處於後期階段，旨在展示 plozasiran 在多個患者群體中的價值。正如我所提到的，我們將 plozasiran 視為單一藥物的管道，這些研究有潛力實現這一點。

Our commercial organization is taking shape, and we have a thoughtful strategy to grow in support of plozasiran as the clinical studies and ultimately the product label grows into progressively larger patient populations.

我們的商業組織正在形成，隨著臨床研究和最終產品標籤逐漸進入更大的患者群體，我們有一個深思熟慮的策略來支持 plozasiran 的發展。

And lastly, we have taken the next steps to execute on our long-term financing strategy and now have a stronger balance sheet, enabling us to better fund innovation and growth opportunities across Arrowhead's robust and diverse pipeline of RNAi therapeutics.

最後，我們已經採取了下一步措施來執行我們的長期融資策略，現在擁有更強大的資產負債表，使我們能夠更好地為Arrowhead 強大而多樣化的RNAi 治療產品線的創新和成長機會提供資金。

We have focused most of this call on plozasiran, but of course, we have a large stable of value drivers under it that continue to move forward. Our pulmonary franchise with three current clinical candidates are muscle franchise with two current clinical candidates and our complement franchise with two current clinical candidates, all continued to progress over the quarter. By the end of the year, we expect to file CTAs in support of two obesity candidates and 2 CNS candidates, and you will hear more about those programs at our webinars on August 14 and September 25, respectively.

我們將這次電話會議的大部分重點放在了 plozasiran 上，但當然，我們有大量穩定的價值驅動因素在繼續向前發展。我們擁有三名當前臨床候選者的肺部特許經營權、擁有兩名當前臨床候選者的肌肉特許經營權以及擁有兩名當前臨床候選者的補充特許經營權，所有這些都在本季度繼續取得進展。到今年年底，我們預計將提交CTA 支持兩名肥胖候選人和兩名中樞神經系統候選人，您將分別在8 月14 日和9 月25 日的網路研討會上聽到有關這些計劃的更多資訊.

Our partner programs also made progress as the Olpasiran Phase 3 against Lp-a is fully enrolled, and the plozasiran Phase 3 against AAT continues to enroll patients. Our HBV and HSD programs with GSK are both in Phase 2 studies, and we continue to weigh our options with the PNPLA3 program that we started with J&J, and we now wholly own. We think these potential value drivers will play an important role in the future of Arrowhead, either as marketed products themselves or part of the steps that we take to bridge plozasiran to commercialization.

我們的合作夥伴計畫也取得了進展，針對 Lp-a 的 Olpasiran 3 期試驗已全面入組，針對 AAT 的 plozasiran 3 期試驗繼續招募患者。我們與葛蘭素史克 (GSK) 合作的 HBV 和 HSD 計畫均處於 2 期研究中，我們將繼續權衡我們與強生 (J&J) 合作啟動的 PNPLA3 計畫的選擇，目前我們已完全擁有該計畫。我們認為這些潛在的價值驅動因素將在 Arrowhead 的未來中發揮重要作用，無論是作為上市產品本身還是我們為將 plozasiran 與商業化聯繫起來所採取的步驟的一部分。

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。現在我想開始回答你們的問題。操作員？

(Operator Instructions) Maury Raycroft, Jefferies.

（操作員說明）Maury Raycroft，Jefferies。

Hi, congrats on the quarter, and thanks for taking my questions. I'm going to start off with FCS. Just wondering if you can provide more perspective on what additional details we should expect to see at the ESC meeting. And the study hit statsig on reducing acute pancreatitis in the small sample size, whereas Ionis didn't show statsig difference, what are your latest thoughts on how your FCS label could look like versus Ionis' Olezarsen?

您好，恭喜本季度，感謝您回答我的問題。我將從 FCS 開始。只是想知道您是否可以提供更多關於我們應該在 ESC 會議上看到哪些額外細節的觀點。這項研究在小樣本量下統計了減少急性胰臟炎的效果，而 Ionis 沒有顯示出統計數據的差異，您對您的 FCS 標籤與 Ionis 的 Olezarsen 標籤相比有何最新想法？

Well, so let's take the first question first. I do expect that the presentation will give much more detail especially on the primary and secondary endpoints, but I think also on -- more broadly on some of the more exploratory or secondary endpoints. But focus, I think, will be on primary and alpha-controlled secondaries, all of which were statistically significant, but most of which haven't really been fully exposed to the investor and scientific communities.

好，那我們先來回答第一個問題。我確實希望演示文稿將提供更多詳細信息，特別是關於主要和次要終點的信息，但我也認為更廣泛地涉及一些更具探索性或次要終點的信息。但我認為，重點將放在初級和阿爾法控制的次級上，所有這些都具有統計顯著性，但其中大多數尚未真正完全暴露給投資者和科學界。

As far as pancreatitis goes, I mean, that's obviously exciting for us. And we're really happy to achieve statistical significance there. And it's going to be, obviously, an important part of our filing with the FDA as well. And it will be interesting to see how they view the data. But we're certainly excited about it.

我的意思是，就胰臟炎而言，這顯然讓我們興奮不已。我們真的很高興在那裡取得了統計顯著性。顯然，這也將成為我們向 FDA 提交文件的重要組成部分。看看他們如何看待數據將會很有趣。但我們當然對此感到興奮。

Got it. And maybe one more quick one. Just are you saying how many patients are enrolled in the Expanded Access Program?

知道了。也許還有一個更快的。您只是說有多少患者參加了擴展訪問計劃？

No, we have not done.

不，我們還沒有做到。

Okay. Thanks for taking my questions. I'll hop back in the queue.

好的。感謝您回答我的問題。我會跳回到隊列中。

Thanks.

謝謝。

Ellie Merle, UBS.

艾莉·梅爾，瑞銀。

Hey, guys. Thanks so much for taking the question. Just what's your latest thinking on the Phase 2 initiation for ARO-RAGE and asthma and the gating factors to getting that started? And can you just remind us the latest time line for when we can expect to see additional data or on any of the preliminary programs in terms of the clinical studies you have ongoing? Thanks.

嘿，夥計們。非常感謝您提出問題。您對 ARO-RAGE 和氣喘的 2 期啟動的最新想法是什麼？您能否提醒我們預計何時可以看到更多數據或您正在進行的臨床研究的任何初步計劃的最新時間表？謝謝。

Yes. Thank you very much for the question. We've not given any more guidance on when we'll have additional data. We'll just see when we can complete those studies and then we will present those when we can. Regarding the Phase 2, we are developing those plans right now. And so stay tuned on more information on that. We -- there are a number of factors that we're weighing about what type of patients we'll be treating and how long we'll be treating, et cetera. And so we are still in the process of working that out right now.

是的。非常感謝你的提問。我們沒有就何時獲得更多數據提供更多指導。我們將看看何時可以完成這些研究，然後我們將在可能的情況下展示這些研究。關於第二階段，我們現在正在製定這些計劃。請繼續關注更多相關資訊。我們正在權衡許多因素，以確定我們將治療哪種類型的患者以及我們將治療多長時間等等。所以我們現在仍在解決這個問題。

Thanks.

謝謝。

You're welcome.

不客氣。

Thank you. One moment for our next question. Our next question comes from Luca Issi from RBC Capital. Please go ahead.

謝謝。請稍等一下我們的下一個問題。我們的下一個問題來自 RBC Capital 的 Luca Issi。請繼續。

Great. Thanks so much for taking the question. Maybe two quick ones. Maybe, Chris or Ken, can you just expand why you think the deal announced today was struck on favorable economics. Can you just maybe help us contextualize the 15% annual interest rate and maybe how you negotiated that?

偉大的。非常感謝您提出問題。也許兩個快點。克里斯或肯，也許您能解釋為什麼您認為今天宣布的交易是在有利的經濟狀況下達成的。您能否幫助我們了解 15% 年利率以及您是如何協商的？

And then maybe on FCS, Bruce, I appreciate you have a differentiated approach here. You're including both genetically as well as clinically confirmed patients with PALISADE. But how should we think about payers? Is it possible that payers would at least initially restrict access to just patients that are genetically confirmed before maybe broadening also to clinically confirm? Any color there, much appreciated. Thanks so much.

然後也許在 FCS 上，Bruce，我很欣賞你在這裡採取了差異化的方法。您包括基因和臨床確診的 PALISADE 患者。但我們該如何考慮付款人呢？付款人是否有可能至少在開始時只限制獲得基因確認的患者，然後再擴大到臨床確認？任何顏色都有，非常感謝。非常感謝。

Sure. So I'll start with the deal and Kim can add if he like. Look, the take home message for us on that was that we are at the point of development in this company that I think we can take on debt, broadly speaking. But it's got to be the right kind of debt. We have an awful lot to do in the coming years to build out our commercial infrastructure before we start to see substantial revenue come in. And so any kind of debt that made sense to us was going to have to be long dated.

當然。所以我將從交易開始，如果 Kim 願意的話，他可以補充。看，對我們來說，最重要的訊息是，我們正處於這家公司的發展階段，我認為從廣義上講，我們可以承擔債務。但它必須是正確的債務類型。在我們開始看到大量收入之前，未來幾年我們還有大量工作要做，以建立我們的商業基礎設施。

The 7-year term makes a lot of sense to us. It gives us plenty of room to bridge. I talked about this bridge to plozasiran, SHTG market. I think that could be in the 2027 or so time frame. And so the 7-year term gets us deep into that, that's comfortable for us.

7年的任期對我們來說意義重大。它給了我們足夠的空間來彌補。我談到了通往 plozasiran、SHTG 市場的這座橋樑。我認為這可能是在 2027 年左右的時間範圍內。因此，7 年任期讓我們深入了解這一點，這對我們來說很舒服。

There's also really attractive risk sharing components here. There's not a coupon here that we need to be paying on a regular basis. We'll be paying this if and only if certain external funds come in, and so it does not put constraints on us that would have been problematic. And so this, to us, feels like a very comfortable and appropriate structure. Ken, do you have anything else you want to add on that?

這裡還有非常有吸引力的風險分擔組件。這裡沒有我們需要定期支付的優惠券。當且僅當某些外部資金進入時我們才會支付這筆費用，因此它不會對我們造成限制，否則會出現問題。因此，對我們來說，這是一個非常舒適且合適的結構。肯，您還有什麼要補充的嗎？

No, I just wanted to say that it is non-dilutive. So we like that aspect of it. And the cost of capital is reasonable given what our cost of equity capital would be.

不，我只是想說它是非稀釋性的。所以我們喜歡它的這一方面。考慮到我們的股權資本成本，資本成本是合理的。

Yes. Actually, let me underline that. I think that's a great point. When we look at what we can be achieving over the coming years, the cost of equity capital at this point feels quite expensive, and this is a very different bad proposition for us. Bruce?

是的。事實上，讓我強調這一點。我認為這是一個很好的觀點。當我們考慮未來幾年可以實現的目標時，此時的股本成本感覺相當昂貴，這對我們來說是一個非常不同的糟糕主張。布魯斯？

Yes. Luca, you asked a very good question. The interesting thing about the way PALISADE was constructed is that if you didn't know the genetics on any of these patients, they'd all look the same. So what we really have here is we have a group of patients that happen to have a narrow set of genetics that characterize them as familial chylomicronemia syndrome or FCS. And then we have a group of patients that basically look the same, but happen to have different genetic makeup. But clinically, they're the same. And that's what's interesting about this.

是的。盧卡，你問了一個很好的問題。 PALISADE 建構方式的有趣之處在於，如果您不知道這些患者的遺傳學，那麼他們看起來都一樣。因此，我們真正擁有的是一群患者，他們碰巧具有一組狹窄的遺傳學特徵，將他們描述為家族性乳糜微粒血症綜合症或 FCS。然後我們有一組看起來基本上相同的患者，但碰巧有不同的基因組成。但在臨床上，它們是相同的。這就是有趣的地方。

So my expectation is that it will really probably come down to what the package insert says. And of course, we don't know that at this point. But I think that the payers will go along with the package insert. And assuming that we get approved and assuming that the agency labels us for the patients that were studied, we would expect that the payers will go along that patients that match our entry criteria, if you will, I think, will be covered. But that will, of course, be payer to payer.

所以我的期望是，它真的很可能取決於包裝說明書上的內容。當然，我們目前還不知道這一點。但我認為付款人會同意包裝說明書。假設我們獲得批准，並假設該機構為我們所研究的患者貼上標籤，我們希望付款人會同意符合我們進入標準的患者，如果你願意的話，我認為，將會被覆蓋。但這當然是付款人對付款人的事。

But it feels like overall, as one of the physicians -- one of the investigators said to me, the patients look the same, whether they have the genetics or not, they're still the same problem I have in my clinic of patients with very high triglycerides at risk for pancreatitis and many of them having pancreatitis, recurrent pancreatitis and dangerous pancreatitis.

但總的來說，正如一位醫生——一位研究人員對我說的那樣，病人看起來都一樣，無論他們是否有遺傳基因，他們仍然和我在我的診所裡遇到的問題一樣。三酸甘油酯非常高，有胰臟炎的風險，其中許多人患有胰臟炎、復發性胰臟炎和危險性胰臟炎。

So from the physician perspective, the patients are very much the same. And that's -- these are adult patients mind you. But there's pretty good reason to think that the payers will go along with the package insert here.

因此，從醫生的角度來看，患者是非常相似的。請注意，這些都是成年患者。但我們有充分的理由相信付款人會同意這裡的包裝說明書。

Got it. Thanks so much.

知道了。非常感謝。

Edward Tenthoff, PSC.

愛德華·滕托夫，PSC。

Great. Thank you very much. And congrats on all the progress. Just a little bit more on plozasiran and with respect to what needs to be done for the NDA filing, where are you guys in the process? And how are things progressing on the CMC side? What are the big steps that still need to be done? Thanks.

偉大的。非常感謝。並祝賀所有的進展。關於 plozasiran 的更多資訊以及 NDA 備案需要做什麼，你們在這個過程中處於什麼位置？中央軍委的進展如何？還需要採取哪些重大措施？謝謝。

Let's see, well, I mean we're busily writing. We will have our pre-NDA meeting with the FDA, and that will give us more insight into whether there's anything special they would like us to do that we're not already doing. CMC is moving along as well. So I mean, we're just in the presubmission phase, I guess, Ted, I don't know how to give you more than that at this point, but we're deep in it.

讓我們看看，好吧，我的意思是我們正在忙著寫作。我們將與 FDA 舉行 NDA 前會議，這將使我們更深入地了解他們是否希望我們做一些我們尚未做的特別事情。 CMC 也在不斷前進。所以我的意思是，我們只是處於提交前階段，我想，Ted，我現在不知道如何給你更多的東西，但我們已經深入了。

Fair. And just remind me, the goal is to follow by year-end?

公平的。請提醒我，目標是在年底前實現？

Yes, that's been the guidance so far.

是的，這是迄今為止的指導。

Thank you. And then a follow-up question, if I may, just on the muscle program. What should we be expecting for in terms of future data in terms of readouts from your muscle programs? Thanks.

謝謝。如果可以的話，接下來的問題是關於肌肉計劃。對於肌肉計劃讀數的未來數據，我們應該期待什麼？謝謝。

Yes. So we've not given any guidance on that. These are still early-ish programs. We are treating patients. We'll see how fast we can treat. We'll see how fast we can generate data that is interpretable. So in other words, don't expect to have a drip, drip of data of onesie-twosie's patients, we need to put them together that would be hopeful to investors once we have it.

是的。所以我們沒有對此給予任何指導。這些仍然是早期的計劃。我們正在治療病人。我們將看看我們能多快治療。我們將看看產生可解釋的數據的速度有多快。換句話說，不要指望得到 onesie-twosie 患者的大量數據，我們需要將它們放在一起，一旦我們掌握了這些數據，這將對投資者充滿希望。

So I don't -- I would not expect data this year. And so we'll see next year when we could have something we just -- we don't know the answer to that at this point. Do you have anything to add on that, James?

所以我不希望今年有數據。因此，我們將看到明年我們何時可以得到一些我們只是 - 目前我們不知道答案的東西。詹姆斯，你還有什麼要補充的嗎？

No, I think --

不，我想——

Great. Thank you --

偉大的。謝謝 -

Right on timing. Suffice it to say that the readouts, I think, will be substantially the same as what others have shown in terms of DMPK, knockdown, splice correction, tissue concentrations, that sort of thing.

準時。我認為，只要說讀數與其他人在 DMPK、敲低、剪接校正、組織濃度等方面顯示的讀數基本上相同就足夠了。

Great. Looking forward to all that. Thanks.

偉大的。期待這一切。謝謝。

Jason Gerberry, Bank of America.

傑森‧格伯里，美國銀行。

Hey, guys, thanks for taking my questions. My first is just on the facility you announced this evening. So is the right way to think about it? I mean you have a business model where you have this unpredictable flow of milestone in the door, so to speak. So this gives you like the flexibility to draw from the facility. But once those milestone payments come in, you can retire or repay and avoid the 15% cost, but it just kind of gives you operational flexibility at that point one.

嘿，夥計們，謝謝你回答我的問題。我的第一個想法是關於您今晚宣布的設施。那麼思考這個問題的方法是正確的嗎？我的意思是，你有一個商業模式，可以這麼說，你在門上有一個不可預測的里程碑流程。因此，這為您提供了從設施中提取資金的靈活性。但是，一旦這些里程碑付款到來，您就可以退休或償還並避免 15% 的成本，但這只是為您提供了當時的營運靈活性。

And then the second question is just on ARO-TSLP I'm wondering, this mechanism, I guess, would seem somewhat redundant with ARO-RAGE. And so just curious I imagine some investors may read through to this impact to your confidence or shouldn't read across your confidence in ARO-RAGE. Just in general, what's your hypothesis around ARO-TSLP differentiating from biologic approaches? Thanks.

然後第二個問題是關於 ARO-TSLP 我想知道，我想這個機制對於 ARO-RAGE 來說似乎有點多餘。因此，我只是好奇，我想一些投資者可能會理解這種對您信心的影響，或者不應該理解您對 ARO-RAGE 的信心。總的來說，您對 ARO-TSLP 與生物方法有何不同的假設是什麼？謝謝。

So let me give the short answer on TSLP, and I'll hand it over to James to give more insight on that. But the reason that we were interested in TSLP, to be totally honest, was not necessarily to have a monomer of TSLP, but we thought it could be a very interesting part of a dimer.

因此，讓我對 TSLP 做一個簡短的回答，然後我將把它交給 James，讓他對此提供更多見解。但說實話，我們對 TSLP 感興趣的原因並不一定是 TSLP 的單體，而是我們認為它可能是二聚體中非常有趣的部分。

As you know, we've been developing our ability to deliver dimers to various tissues. And so we did it for that reason. And so it may be part of dimer at some point, we're still exploring that. But that was the primary reason. I don't -- we were not planning on bringing that in as a monomer necessarily.

如您所知，我們一直在開發將二聚體遞送至各種組織的能力。因此我們就是出於這個原因這樣做的。因此它可能在某個時候成為二聚體的一部分，我們仍在探索這一點。但這是主要原因。我不知道——我們並不打算將其作為單體引入。

I think that's right. We were not planning on bringing the ARO-TSLP program forward by itself. And then mechanistically, I mean, RAGE, if you look at the cascade, inflammatory cascade, RAGE sits upstream of TSLP, but there's -- in terms of the disease indications at least for asthma that you could go after and they're very similar.

我認為這是對的。我們並不打算單獨推進 ARO-TSLP 計劃。然後從機制上講，我的意思是，RAGE，如果你觀察級聯、發炎級聯，RAGE 位於 TSLP 的上游，但就疾病適應症而言，至少對於氣喘，你可以追求它們，而且它們非常相似。

And regarding the facility, yes, I'm sure it gives us flexibility. But really, it's a piece of this bridge that we're talking about. We need to bring in enough capital to allow us to continue to build over the next few years, while we're waiting to hopefully address the SHTG market with plozasiran, that I think we'll be -- we'll bring with a substantial revenue.

關於設施，是的，我確信它給我們帶來了靈活性。但實際上，我們正​​在談論的是這座橋的一部分。我們需要引入足夠的資金，使我們能夠在未來幾年繼續建設，同時我們正在等待希望透過 plozasiran 解決 SHTG 市場問題，我認為我們將帶來大量資金收入。

And this is just one of those pieces. It's not the only piece. We still expect to do business development deals. Some of those may be partially used to pay out facility, but a good chunk of it may not be, we may just be using that for operational purposes. So think of it that way, that it's one of many ways that we -- or one of many tools that we expect to use to build that bridge.

這只是其中之一。這不是唯一的一塊。我們仍然期望進行業務開發交易。其中一些可能部分用於支付設施，但其中很大一部分可能不是，我們可能只是將其用於營運目的。因此，可以這樣想，這是我們希望用來建造這座橋樑的多種方式之一，或者是我們期望用來建造這座橋樑的多種工具之一。

Got it. Thanks a lot.

知道了。多謝。

Mayank Mamtani, B. Riley Financial.

Mayank Mamtani，B. Riley Financial。

Hey, guys. [Madison Owen] for Mayank. Thank you for taking our questions. So a couple of quick ones from me. Is there anything you're closely monitoring within the neuro muscle landscape that may influence your development plans for ARO-DM1 and DUX4, especially kind of on the regulatory front?

嘿，夥計們。 [麥迪遜歐文]為 Mayank。感謝您接受我們的提問。這是我的一些快速的。您正在密切監測的神經肌肉領域是否有任何事情可能會影響您的 ARO-DM1 和 DUX4 開發計劃，尤其是在監管方面？

And then secondly, regarding the dimers, is there, I guess, time line to when something like that could be in the clinic? And is there an indication or target where you think this is better suited than others? Thank you.

其次，關於二聚體，我想，類似的東西何時可以進入臨床，是否有時間軸？您認為這是否比其他方法更適合的指示或目標？謝謝。

James, do you want to address the muscular question?

詹姆斯，你想解決肌肉問題嗎？

Yes, sure. I mean I don't know that there's any specific one item from a regulatory standpoint or neuromuscular developments that we're following. Suffice it to say that we follow all of the other programs that are out there very closely and use the data that come out in the literature and from our competitors to guide our own programs.

是的，當然。我的意思是，我不知道從監管角度或我們正在關注的神經肌肉發展來看，有任何具體的一項。可以說，我們非常密切地關注所有其他項目，並使用文獻中和競爭對手提供的數據來指導我們自己的項目。

Yes. Look, our position there, from my perspective, is a real pleasure to be totally honest, you know, between HBV and AAT and so many others, we are the first ones to blaze the trail. And so there are certain advantages to be first, but there are certain vulnerabilities as well. And so we get to learn from competitors' interactions with regulatory agencies, et cetera. And so look, our job is to be best-in-class. Presumably, we'll have a road map that's sort of laid out for us. And our job is just to have better drugs. We are hopeful that we can have those.

是的。聽著，從我的角度來看，我們在那裡的地位是一種真正的快樂，完全誠實，你知道，在 HBV 和 AAT 以及許多其他人之間，我們是第一個開闢道路的人。因此，成為第一名有一定的優勢，但也存在一定的弱點。因此，我們可以從競爭對手與監管機構的互動等中學習。所以看，我們的工作就是成為一流的。據推測，我們將會有一個為我們制定的路線圖。我們的工作就是擁有更好的藥物。我們希望能夠擁有這些。

Regarding the dimers, we haven't given any real guidance on dimers other than during the cardiometabolic day we talked about or what I expect will be our first dimer in the clinic. The PCSK9, APOC3 dimer, we're excited about that. That will not be in the clinic this year, but I would expect that to be in the clinic next year. We have not talked about where else we are going with dimers in the near term.

關於二聚體，除了我們討論的心臟代謝日或我預計將是我們在臨床上的第一個二聚體之外，我們還沒有對二聚體給出任何真正的指導。 PCSK9、APOC3 二聚體，我們對此感到興奮。今年不會在診所使用，但我預計明年就會在診所使用。我們還沒有討論短期內我們還將二聚體用於何處。

As you can imagine, the lower-hanging fruit with dimers, of course, is delivery to hepatocytes. And so I would expect those to be first. And then as our technologies mature, we can start to think about that type of strategy for other tissue types.

正如您可以想像的那樣，二聚體的唾手可得的成果當然是輸送到肝細胞。所以我希望這些是第一位的。然後，隨著我們的技術成熟，我們可以開始考慮針對其他組織類型的此類策略。

Got it. Thank you. And if I could squeeze in to the -- your adipose tissue targeting. Is there a time line on that? Could you remind us on that time line?

知道了。謝謝。如果我能擠進去——你的脂肪組織目標。那有時間線嗎？您能提醒我們一下那個時間嗎？

Well, so tune into our webinar on August 14, you'll hear our first adipose target that we're going after, and we expect that to be -- we expect to file a CTA for that this year. We have not given guidance on what those are yet, but you'll hear at least that one next week, I guess.

那麼，請收看我們 8 月 14 日的網路研討會，您會聽到我們正在追求的第一個脂肪目標，我們預計今年會為此提交一份 CTA。我們還沒有就這些內容提供指導，但我想您至少會在下週聽到這一訊息。

Got it. Congrats on the progress, guys.

知道了。恭喜你們取得了進步。

Thank you.

謝謝。

Mani Foroohar, Leerink Partners.

Mani Foroohar，Leerink 合夥人。

Hi. Good afternoon, everyone. This is CJ Yeh on for Mani. My question is on the credit facility with Sixth Street. I understand there's no scheduled amortization payments, but could you give a little detail on what proportion of future upfront payments, milestones or royalties from partnerships or Cosme have to go towards repaying the loan? That would be appreciated.

你好。大家下午好。這是 Mani 的 CJ Yeh。我的問題是關於第六街的信貸安排。據我所知，沒有預定的攤銷付款，但您能否詳細說明未來預付款、里程碑或合夥企業或 Cosme 的特許權使用費中必須用於償還貸款的比例是多少？我們將不勝感激。

Sure. Yes, I can take that. So it depends on which particular asset it is. This is a very custom structure that we went through. And so we kind of bucketed different assets, and each of those has different payback economics. So the philosophy here is that we wanted the flexibility to spread out repayment of this over time. And we also didn't want to have too much of a cash outlay obligation unless we were going to have a significant cash inflow with the corresponding with what you're talking about with potential upfront payments from new deals or milestone payments or royalties from existing deals. So there's various different levels for different assets.

當然。是的，我可以接受。因此，這取決於它是哪種特定資產。這是我們經歷過的一個非常客製化的結構。因此，我們投資了不同的資產，每種資產都有不同的報酬經濟學。因此，這裡的理念是，我們希望能夠靈活地隨著時間的推移分期償還。我們也不希望有太多的現金支出義務，除非我們將有大量的現金流入，與您所說的新交易或里程碑付款或現有特許權使用費的潛在預付款相對應。因此，不同的資產有不同的等級。

Okay. And some are zero?

好的。還有一些是零？

There will be some transactions where we aren't required to pay any portion of that 60.

在某些交易中，我們不需要支付這 60 美元的任何部分。

That's right. And we pre-negotiated the carve-outs for a handful of things that we think are likely over the coming years.

這是正確的。我們也就一些我們認為未來幾年可能發生的事情進行了預先談判。

Got it. Would you be able to disclose whether these tend to be more like front loaded or back loaded in terms like the proportion of those future collections that would have to go to repaying the loan?

知道了。您能否透露這些是否更像是前裝還是後裝，例如未來收款中必須用於償還貸款的比例？

No, we're not. We're not giving more guidance on that at this point. But we will file a redacted version of the contract at some point. But at this point, we're just disclosing what was in the press release.

不，我們不是。目前我們不會就此提供更多指引。但我們將在某個時候提交合約的修訂版本。但目前，我們只是揭露新聞稿中的內容。

Okay, sounds good. Thanks so much for taking your question.

好吧，聽起來不錯。非常感謝您提出問題。

Welcome.

歡迎。

Thank you. One moment for our next question. Our next question comes from Brendan Smith from TD Cowen. Please go ahead.

謝謝。請稍等一下我們的下一個問題。我們的下一個問題來自 TD Cowen 的 Brendan Smith。請繼續。

Hi, guys. Thanks for taking the questions. Just a quick one for me. Kind of given this latest financing, can you give us a sense of how you're thinking about additional partnerships this year? Should we expect you'll announce a commercialization partner sometime in 2024? Or is that maybe a next year at this point? And then just really quickly, I wanted to ask if you're still planning to release Phase 1 data with that ARO CFB this year and kind of just how you're thinking about next steps and potential indications for that one? Thanks.

嗨，大家好。感謝您提出問題。對我來說只是一個快速的。鑑於最新的融資，您能否告訴我們您如何考慮今年的更多合作關係？我們是否應該期望你們會在 2024 年的某個時候宣布商業化合作夥伴？或者現在可能是明年？然後很快，我想問一下，您是否仍計劃今年發布 ARO CFB 的第一階段數據，以及您如何考慮後續步驟和該步驟的潛在跡象？謝謝。

James, do you want to talk about --

詹姆斯，你想談談——

Sure. We should be in a position to release data from the CFB program later this year. And then the primary additional indications that we're looking at, of course, the study starts in healthy volunteers, but we will also be looking at ARO CFB in patients with IgA nephropathy in the study.

當然。我們應該能夠在今年稍後發布 CFB 計劃的數據。當然，我們正在研究的主要附加適應症是從健康志願者開始的，但我們還將在研究中研究 IgA 腎病患者的 ARO CFB。

Sorry, what was the first question?

抱歉，第一個問題是什麼？

Timing on partnerships?

合作夥伴關係的時機？

That's easy. I can't predict timing on partnerships. We are -- as one can imagine, we have a lot going on. And so we are actively speaking with companies all the time, who knows how fast those go, who knows, that's our timing. So look, these are priorities for us, but I can't give you a timing.

這很容易。我無法預測合作關係的時間。正如人們可以想像的那樣，我們正在發生很多事情。因此，我們一直在積極與公司對話，誰知道這些公司進展得有多快，誰知道，這就是我們的時機。所以看，這些是我們的優先事項，但我無法給你一個時間安排。

Thank you. One moment for our next question. Our next question comes from William Pickering from Bernstein. Please go ahead.

謝謝。請稍等一下我們的下一個問題。我們的下一個問題來自伯恩斯坦的威廉·皮克林。請繼續。

Hi, good afternoon. Thank you so much for taking my question. I noticed there was about a $50 million sequential increase in the R&D this quarter. Could you just give a bit more color on what's in there and how would you expect the R&D line for the next few quarters to compare to that number this quarter? Thank you.

嗨，下午好。非常感謝您回答我的問題。我注意到本季的研發費用較上季增加了約 5,000 萬美元。您能否詳細說明其中的內容以及您預計未來幾季的研發線與本季的數字相比如何？謝謝。

So the increase in R&D, it's been increasing all year as we move these assets further into later stages, and you will expect those to continue to increase into next year. We are going through our budgeting process right now, and we will provide additional guidance at our next earnings call to give you more information on that.

因此，隨著我們將這些資產進一步轉移到後期階段，研發的增加全年都在增加，您會預期這些資產將繼續增加到明年。我們目前正在製定預算流程，我們將在下次財報電話會議上提供更多指導，以便為您提供更多相關資訊。

Thank you.

謝謝。

Thank you. I am showing no further questions at this time. I will turn it back over to Chris Anzalone for closing remarks.

謝謝。我目前沒有提出任何進一步的問題。我將把它轉回克里斯·安扎龍 (Chris Anzalone) 作結束語。

Thank you, everyone, for joining us today, and I hope you have an enjoyable rest of your summer.

謝謝大家今天加入我們，希望你們有個愉快的暑假。

Thank you for your participation in today's conference. This does conclude the program. You may now disconnect.

感謝您參加今天的會議。這確實結束了該程式。您現在可以斷開連線。