Arrowhead Pharmaceuticals Inc (ARWR) 2024 Q2 法說會逐字稿

Ladies and gentlemen, welcome to the Arrowhead Pharmaceuticals conference call.

女士們、先生們，歡迎參加 Arrowhead Pharmaceuticals 電話會議。

Throughout today's recorded presentation. all participants will be in a listen only mode.

貫穿今天的錄製示範。所有參與者將處於只聽模式。

After the presentation there will be an opportunity to ask a question.

演講結束後，將有機會提問。

(Operator Instructions)

（操作員說明）

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

我現在將電話會議交給 Arrowhead 投資者關係副總裁 Vince Anzalone。

Please go ahead.

請繼續。

Thank you.

謝謝。

Good afternoon, everyone, and thank you for joining us today to discuss Arrowhead's results for its fiscal 2024 second quarter ended March 31, 2024.

大家下午好，感謝您今天加入我們討論 Arrowhead 截至 2024 年 3 月 31 日的 2024 財年第二季度業績。

With us today from management are President and CEO, Dr. Chris Anzalone, who will provide an overview of the quarter; Dr. Bruce Given . our Interim Chief Medical Scientist, who will provide an update on our cardiometabolic pipeline; Dr. James Hamilton, our Chief of Discovery and Translational Medicine will provide an update on our earlier-stage programs, and Ken Myszkowski, our Chief Financial Officer, will give a review of the financials.

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；布魯斯·吉文博士。我們的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；我們的發現和轉化醫學主管 James Hamilton 博士將提供我們早期項目的最新信息，我們的首席財務官 Ken Myszkowski 將審查財務狀況。

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 27 A of the Securities Act of 1933 and Section 21 E. of the Securities Exchange Act of 1934.

在開始之前，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 27 A 條和 1934 年《證券交易法》第 21 E 條含義內的某些前瞻性陳述。

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.

除歷史事實陳述外的所有陳述均為前瞻性陳述，並受到眾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。

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.

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.

我現在想將電話轉給公司總裁兼執行長 Chris Anzalone。

Chris?

克里斯？

Thanks, Vince.

謝謝，文斯。

Good afternoon, everyone, and thank you for joining us today.

大家下午好，感謝您今天加入我們。

As we discussed in our last conference call, Arrowhead has reached a point where our business requires a greater degree of focus.

正如我們在上次電話會議中討論的那樣，Arrowhead 已經達到了我們的業務需要更加關注的地步。

We are in the process of building out our expertise within the cardiometabolic space and focusing more of our spend in that area.

我們正在建立我們在心臟代謝領域的專業知識，並將更多的支出集中在該領域。

These are wholly appropriate actions because our cardiometabolic programs represent a substantial amount of potential near mid and long-term value.

這些都是完全適當的行動，因為我們的心臟代謝計畫代表著近中長期的大量潛在價值。

We need to ensure that they are properly resourced, both from a financial and human capital standpoint and that they are at the center of investor analysis of our business.

從財務和人力資本的角度來看，我們需要確保他們擁有適當的資源，並確保他們處於投資者對我們業務分析的中心。

This is a good thing for Arrowhead.

這對箭頭來說是件好事。

We have two late-stage drug candidates with data across diverse populations from ultra rare to highly prevalent spanning over 1,000 human subjects.

我們有兩種處於後期階段的候選藥物，其數據涉及從超罕見到高度流行的不同人群，涵蓋 1,000 多名人類受試者。

We see a train of potential value creation with both plozasiran and zodasiran and expect to file NDAs or supplements to expand those labels almost every year over the next five to six years.

我們看到 plozasiran 和 zodasiran 都具有一系列潛在的價值創造，並預計在未來五到六年內幾乎每年都會提交 NDA 或補充文件以擴大這些標籤。

This is a pipeline within just two drugs, and I believe we will start unlocking value in the very near term.

這是一個只有兩種藥物的管道，我相信我們將在不久的將來開始釋放價值。

Further, we expect to expand our cardiometabolic reach into obesity and metabolic disease with two additional drug candidates reaching the clinic this year.

此外，我們預計今年將有另外兩種候選藥物進入臨床，將我們的心臟代謝領域擴大到肥胖和代謝疾病。

The plozasiran PALISADE Phase 3 study in patients with familial chylomicronemia syndrome or FCS is clinically complete.

針對家族性乳糜微粒血症症候群或 FCS 患者的 plozasiran PALISADE 3 期研究已臨床完成。

The last patient last visit occurred last week.

最後一位患者的最後一次就診發生在上週。

The database should be locked over the next two weeks, and I expect to disclose top line data at our cardiometabolic webinar in June with a fuller dataset hopefully presented this year and appropriate medical conference.

該資料庫應在接下來的兩週內鎖定，我預計將在六月的心臟代謝網路研討會上披露最重要的數據，並希望在今年和適當的醫學會議上提出更完整的數據集。

We believe that plozasiran will become our first commercial product, and we are preparing for an NDA submission for use in FCS patients by the end of the year with a potential launch in 2025.

我們相信 plozasiran 將成為我們的第一個商業產品，我們正在準備在今年年底之前提交用於 FCS 患者的 NDA 申請，並可能在 2025 年推出。

To this end, our commercial preparations are well underway.

為此，我們的商業準備工作正在有條不紊地進行。

We have begun building our commercial team, including people with deep expertise in cardiometabolic marketing, commercial operations and market access.

我們已經開始建立我們的商業團隊，包括在心臟代謝行銷、商業營運和市場准入方面擁有深厚專業知識的人員。

We're also in the later stages of solidifying a specialty pharma and patient hub system that will be ready to help ensure FCS patients get plozasiran soon after its anticipated approval.

我們也處於鞏固專業製藥和患者中心系統的後期階段，該系統將準備好幫助確保 FCS 患者在預期批准後盡快獲得 plozasiran。

Beyond our commercial infrastructure.

超越我們的商業基礎設施。

We have begun building out our medical affairs team, with a focus on field support to help clinicians better understand APOC3 inhibition.

我們已經開始建立我們的醫療事務團隊，重點是現場支持，以幫助臨床醫生更好地了解 APOC3 抑制。

Additionally, we have begun helping physicians who request early access to plozasiran to do so for appropriate FCS patients prior to approval.

此外，我們已經開始幫助那些要求儘早使用 plozasiran 的醫生在批准之前為適當的 FCS 患者這樣做。

We are also studying plozasiran in the broader severe hypertriglyceridemia, or SHTG population.

我們也正在更廣泛的嚴重高三酸甘油酯血症（SHTG）族群中研究 plozasiran。

Toward that end, we have begun screening patients in two Phase 3 studies, SHASTA-3 and SHASTA-4 and are preparing a third Phase 3 in SHASTA-5.

為此，我們已開始在兩項 3 期研究 SHASTA-3 和 SHASTA-4 中篩選患者，並正在準備 SHASTA-5 中的第三項 3 期研究。

Of course, it is early, but our aggressive goal is to complete enrollment of those studies in 2025.

當然，現在還為時過早，但我們的雄心勃勃的目標是在 2025 年完成這些研究的註冊。

SHASTA-3 and SHASTA-4 are 52-week studies and SHASTA-5 is an acute pancreatitis study that will follow patients until a set number of pancreatitis events is reached.

SHASTA-3 和 SHASTA-4 是為期 52 週的研究，SHASTA-5 是一項急性胰臟炎研究，將追蹤患者直至達到設定的胰臟炎事件數量。

Turning to zodasiran, we submitted briefing documents including Phase 3 study designs for patients with homozygous familial hypercholesterolemia or HoFH to the FDA and expect an end of Phase 2 meeting this month.

談到 zodasiran，我們向 FDA 提交了簡報文件，包括針對純合子家族性高膽固醇血症或 HoFH 患者的第 3 期研究設計，並預計第 2 期會議將於本月結束。

We hope to initiate Phase 3 soon after we receive regulatory feedback.

我們希望在收到監管回饋後儘快啟動第三階段。

We have also completed our analysis of how to move forward in the large mixed dyslipidemia population with a cardiovascular outcomes trial or CVOT.

我們也完成瞭如何透過心血管結果試驗或 CVOT 在大型混合性血脂異常人群中取得進展的分析。

We have submitted our proposal to the FDA and expect feedback over the next month and then we'll seek input from the EMA and other regulatory authorities.

我們已向 FDA 提交了提案，希望在下個月得到回饋，然後我們將尋求 EMA 和其他監管機構的意見。

Will provide detailed information about our plans, expected timing and costs once we know we have regulatory alignment on design.

一旦我們知道我們的設計符合監管要求，我們將提供有關我們的計劃、預期時間和成本的詳細資訊。

Plozasiran and zodasiran are important candidates for us because they offer new and expanding commercial opportunities over the next several years and because clinical data have suggested that they have a higher probability of success.

Plozasiran 和 zodasiran 對我們來說是重要的候選藥物，因為它們在未來幾年提供了新的和不斷擴大的商業機會，而且臨床數據表明它們有更高的成功機率。

Bruce will talk more specifically about results, but a lot of data have been presented recently, and we have been encouraged by the safety and tolerability target engagement, measured and downstream changes in lipids and lipoproteins across multiple patient populations.

布魯斯將更具體地談論結果，但最近已經提供了大量數據，我們對安全性和耐受性目標參與、多個患者群體中脂質和脂蛋白的測量和下游變化感到鼓舞。

As I mentioned, over 1,000 people have enrolled in plozasiran and zodasiran clinical studies.

正如我所提到的，已有 1,000 多人參加了 plozasiran 和 zodasiran 臨床研究。

Safety and tolerability data have given us confidence that these could be appropriate therapeutics, not only for small and medium-sized populations, but also importantly, broad mixed dyslipidemia populations.

安全性和耐受性數據讓我​​們相信，這些可能是合適的治療方法，不僅適用於中小型人群，而且重要的是，適用於廣泛的混合性血脂異常人群。

Target engagement measured by circulating protein knockdown of APOC3, for plozasiran and ANGPTL3 for zodasiran and have been impressive and consistent exact numbers will vary a bit depending on the study population, duration of treatment, dose level and measurement time point.

透過敲除plozasiran 的APOC3 和zodasiran 的ANGPTL3 的循環蛋白敲低來測量標靶參與度，結果令人印象深刻且一致，確切的數字會根據研究人群、治療持續時間、劑量水平和測量時間點的不同而略有不同。

However, we are consistently seeing mean max knockdown exceeding 75% to 90% with a long duration of effect that supports a quarterly dosing interval for plozasiran and zodasiran.

然而，我們始終看到平均最大擊倒率超過 75% 至 90%，且作用持續時間長，支持 plozasiran 和 zodasiran 每季度給藥一次。

And this is what we designed the programs to achieve.

這就是我們設計程式的目的。

So we are very encouraged to see clinical results consistent with our expectations.

因此，看到臨床結果與我們的預期一致，我們感到非常鼓舞。

The downstream change in various lipids and lipoproteins have been favorable and consistent with published genetic data in APOC3 and ANGPTL3 deficient humans and consistent with experimental data in animals receiving APOC3 and ANGPTL3 inhibitors,

各種脂質和脂蛋白的下游變化是有利的，與已發表的 APOC3 和 ANGPTL3 缺陷人類遺傳數據一致，也與接受 APOC3 和 ANGPTL3 抑制劑的動物實驗數據一致，

Similar to target engagement the exact changes varied a bit between different study populations.

與目標參與度類似，不同研究人群之間的確切變化略有不同。

But generally speaking, subjects treated with plozasiran or zodasiran showed improvements in multiple atherogenic lipid and lipoprotein levels, including remnant cholesterol, which is increasingly viewed as an important target for new therapies to address atherosclerotic cardiovascular disease or ASCVD.

但一般來說，接受plozasiran 或zodasiran 治療的受試者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，這越來越被視為解決動脈粥樣硬化性心血管疾病或ASCVD 新療法的重要目標。

Numerous epidemiological studies have shown an association through higher triglycerides proteins or TRLs and an increased risk of ASCVD.

大量流行病學研究表明，較高的三酸甘油酯蛋白或 TRL 與 ASCVD 風險增加存在關聯。

Despite potent LDL-cholesterol lowering therapies, residual ASCVD risk persists due in part to high levels of atherogenic TRLs.

儘管有有效的低密度脂蛋白膽固醇降低療法，但殘餘 ASCVD 風險仍然存在，部分原因是高水平的致動脈粥樣硬化 TRL。

Remnant cholesterol is also believed to be a major contributor to the residual risk of atherosclerotic sclerosis cardiovascular disease after LDL is well controlled.

殘餘膽固醇也被認為是低密度脂蛋白得到良好控制後動脈粥狀硬化性心血管疾病殘餘風險的主要貢獻者。

We believe with plozasiran and zodasiran represent significant opportunities to help a lot of patients for all the reasons I mentioned, we are moving as quickly as possible to our treatments in FCS, HoFH, high risk HeFH, SHTG and the very large population of patients with ASCVD due to mixed dyslipidemia.

我們相信，由於我提到的所有原因， plozasiran 和 zodasiran 代表了幫助大量患者的重要機會，我們正在盡快開展對 FCS、HoFH、高風險 HeFH、SHTG 和大量患有 FCS 的患者的治療。導致ASCVD。

We believe we can help a large number of patients and create a substantial amount of value with plozasiran and zodasiran alone.

我們相信，僅靠 plozasiran 和 zodasiran 可以幫助大量患者並創造大量價值。

However, it makes sense to leverage our growing cardiometabolic capabilities by expanding the vertical.

然而，透過擴展垂直領域來利用我們不斷增長的心臟代謝能力是有意義的。

We expect to introduce two new candidates into the clinic in the fourth quarter aimed at obesity and metabolic disease.

我們預計在第四季度將兩種新的候選藥物引入臨床，針對肥胖和代謝疾病。

These are ARO-INHBE, liver-directed candidate targeting Inhibin E and an undisclosed candidate targeting adipose directly.

它們是 ARO-INHBE、針對抑制素 E 的肝臟導向候選藥物和直接針對脂肪的未公開候選藥物。

We will discuss those in more depth during a focused webinar in the summer.

我們將在夏季的重點網路研討會上更深入地討論這些問題。

We continue to make progress beyond the cardiometabolic vertical as well.

我們也在心臟代謝垂直領域繼續取得進展。

Within pulmonary, the ARO-MMP7 and ARO-MUC5AC Phase 1 studies continue to enroll patients and ARO-RAGE Phase 1 study is enrolling high FeNO patients with moderate to severe asthma.

在肺部領域，ARO-MMP7 和 ARO-MUC5AC 1 期研究繼續招募患者，ARO-RAGE 1 期研究正在招募患有中度至重度氣喘的高 FeNO 患者。

The FeNO cohorts have been slow to enroll because the high baseline FeNO required of the study has led to a high screen fail rate.

FeNO 隊列的入組進展緩慢，因為研究所需的高基線 FeNO 導致了高篩選失敗率。

We believe in the candidate and the target engagement data has been what we had hoped for.

我們相信候選人，目標參與數據也正是我們所希望的。

So we are not going to wait for that to read out before progressing to a Phase 2 study.

因此，我們不會等到結果出來才進行第二階段研究。

We have designed a Phase 2 study in asthma patients and are moving toward launching that in the fourth quarter.

我們已經針對氣喘患者設計了一項 2 期研究，並計劃在第四季度啟動研究。

ARO-RAGE tolerability has been good in the Phase 1 study, we have seen clear evidence of substantial target engagement in the Phase 1 and data in animal models were very encouraging.

ARO-RAGE 的耐受性在 1 期研究中表現良好，我們在 1 期研究中看到了大量目標參與的明確證據，動物模型中的數據非常令人鼓舞。

The rage pathway has also generated a good amount of KOL interest.

憤怒途徑也引起了大量 KOL 的興趣。

So we are excited to move forward as quickly as we can.

因此，我們很高興能夠盡快向前推進。

Moving to our new programs.

轉向我們的新計劃。

During the last quarter, we began dosing in two new clinical programs, ARO-CFB for the treatment of disease diseases associated with activation of the complement pathway and ARO-DM1 for the treatment of type one myotonic dystrophy or DM1.

上個季度，我們開始在兩個新的臨床計畫中給藥，ARO-CFB 用於治療與補體途徑活化相關的疾病，ARO-DM1 用於治療一型強直性肌肉營養不良或 DM1。

These programs put well with ARO-C3 and ARODUX4, respectively.

這些程序分別與 ARO-C3 和 ARODUX4 配合良好。

The former is enrolling the patient portion of a Phase 1/2 study.

前者正在招募 1/2 期研究的患者部分。

And together with ARO-CFB provides a focused portfolio in complement mediated diseases.

與 ARO-CFB 一起提供針對補體介導疾病的重點產品組合。

ARO-DUX4 is enrolling FSHD patients in a Phase 1/2 study.

ARO-DUX4 正在招募 FSHD 患者參加 1/2 期研究。

And together with ARO-DM1 creative focused skeletal muscle portfolio.

並與 ARO-DM1 一起創意專注於骨骼肌組合。

We now have 14 clinical stage programs, 10 of which are wholly owned.

我們現在擁有14個臨床階段項目，其中10個是全資項目。

I expect we could have 18 clinical programs by the end of the year.

我預計到今年年底我們可以有 18 個臨床項目。

This is a lot and they certainly can be difficult to track and properly valued by investors.

這是一個很大的數字，投資者肯定很難追蹤和正確評估它們。

We think of our wholly owned assets in a series of verticals.

我們將我們的全資資產視為一系列垂直領域的資產。

As we have discussed, the cardiometabolic vertical is our primary focus, but beyond that we have: a pulmonary vertical, a complement vertical, a muscular disease vertical; and by the end of the year, a CNS vertical.

正如我們所討論的，心臟代謝垂直是我們的主要關注點，但除此之外，我們還有：肺部垂直、補體垂直、肌肉疾病垂直；到今年年底，將推出 CNS 垂直產品。

We expect to partner with in these four verticals in order to limit our spend and bring in capital to properly fund our cardiometabolic vertical and our other research programs.

我們希望在這四個垂直領域進行合作，以限制我們的支出並引入資金，為我們的心臟代謝垂直領域和其他研究項目提供適當的資金。

But we believe this is the way investors should look at our pipeline understanding and properly valuing these assets can still be difficult.

但我們認為，投資者應該以這種方式看待我們的管道理解，並且正確評估這些資產仍然很困難。

So we recently announced the upcoming 2024 summer series of R&D webinars to highlight some of our work.

因此，我們最近宣布即將舉行 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。

Starting this month and continuing each month through September, we will host five webcast events.

從本月開始，一直到九月，我們將舉辦五場網路廣播活動。

Each event will feature presentations by Arrowhead team members and external key opinion leaders who will discuss disease areas and treatment landscapes.

每場活動都將由 Arrowhead 團隊成員和外部關鍵意見領袖進行演講，他們將討論疾病領域和治療前景。

We will talk about Arrowhead's candidates, the biological rationale and preclinical data supporting each candidate and our clinical development strategy for each pipeline program.

我們將討論 Arrowhead 的候選藥物、支持每個候選藥物的生物學原理和臨床前數據以及我們每個管道項目的臨床開發策略。

For series is designed to highlight important value drivers in a focused way.

For系列旨在以集中的方式突顯重要的價值驅動因素。

The summer series schedule is as follows; May 23 is muscle vertical day where we will cover r ARO-DM1 and ARODUX4.

夏季系列賽日程如下； 5 月 23 日是肌肉垂直日，我們將介紹 r ARO-DM1 和 ARODUX4。

For June 25 is cardio-metabolic day, where we will give an overview of both plozasiran and zodasiran data to date, including Phase 3 PALISADE FCS data and talk about the future of the programs and the diseases we aim to treat.

6 月 25 日是心臟代謝日，我們將概述迄今為止的 plozasiran 和 zodasiran 數據，包括 3 期 PALISADE FCS 數據，並討論該計畫的未來以及我們旨在治療的疾病。

July 16 is pulmonary date, which includes ARO-RAGE, ARO-MUC5AC, and ARO-MMP7.

7 月 16 日是肺部日期，其中包括 ARO-RAGE、ARO-MUC5AC 和 ARO-MMP7。

August 15 is obesity and metabolic disease day where we will talk about ARO-INHBE and the undisclosed adipose candidates.

8 月 15 日是肥胖和代謝疾病日，我們將討論 ARO-INHBE 和未公開的脂肪候選藥物。

And September 25 is CNS Day, where we will highlight our central nervous system programs, including updates on the platform and on a specific undisclosed candidate plans to enter clinical development later this year.

9 月 25 日是中樞神經系統日，我們將重點介紹我們的中樞神經系統項目，包括平台的更新以及今年稍後進入臨床開發的特定未公開候選方案的更新。

In addition to the summer series, we also recently announced a busy month of presentations at medical and scientific meetings.

除了夏季系列之外，我們最近還宣布了繁忙的一個月在醫學和科學會議上的演講。

These include presentations at TIDES USA, the American Thoracic Society 2024 international conference, the International Conference on Antiviral Research, European Atherosclerosis Society Congress in the National Lipid Association scientific sessions.

其中包括在 TIDES USA、美國胸腔科學會 2024 年國際會議、國際抗病毒研究會議、歐洲動脈粥狀硬化協會大會和國家脂質協會科學會議上的演講。

These are all planned for May.

這些都是五月計劃的。

In addition, we plan to present on many of our programs at several medical meetings throughout the year.

此外，我們計劃在全年的幾次醫學會議上展示我們的許多項目。

We have a lot going on, including a lot of exciting results to talk about.

我們有很多事情要做，包括很多令人興奮的結果值得討論。

During the last few months we've also strengthened our balance sheet with two inflows.

在過去的幾個月裡，我們也透過兩次資金流入加強了我們的資產負債表。

The first was out in January when we announced an equity financing with gross proceeds of $450 million.

第一個是在一月份，當時我們宣布進行股權融資，總收益為 4.5 億美元。

The second was just announced last week that was 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.

第二項是上週剛宣布的，是在安進 (Amgen) 進行的 olpasiran 3 期 OCEAN(a) 結果試驗完成入組後，我們從royalty Pharma 收到的 5000 萬美元里程碑付款。

We originally license olpasiran, previously called AROLPA to Amgen in 2016 and then monetize our future royalty stream a transaction with Royalty Pharma in 2022.

我們最初在 2016 年將 olpasiran（以前稱為 AROLPA）授權給安進，然後在 2022 年透過與 Royalty Pharma 的交易將我們未來的特許權使用費貨幣化。

Arrowhead is further eligible to receive up to an additional $375 million from Amgen and $110 million from Royalty Pharma in aggregate development, regulatory and sales milestone payments associated with will pass around.

Arrowhead 還有資格從 Amgen 獲得高達 3.75 億美元的額外資金，並從 Royalty Pharma 獲得 1.1 億美元的額外資金，用於與轉交相關的開發、監管和銷售里程碑付款總額。

This is a good example of how we use partnering and creative financing structures as important parts of our long-term financing strategy.

這是我們如何利用合作夥伴和創意融資結構作為我們長期融資策略的重要組成部分的一個很好的例子。

We are always working on potential future deals and now is no exception.

我們一直致力於未來潛在的交易，現在也不例外。

We are confident that we can complete additional transactions this year to further strengthen our balance sheet, support future clinical development and commercialization of our wholly owned programs.

我們有信心今年能夠完成更多交易，以進一步加強我們的資產負債表，支持我們全資項目的未來臨床開發和商業化。

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

有了這個概述，我現在想把電話轉給布魯斯。

Bruce?

布魯斯？

Thank you, Chris.

謝謝你，克里斯。

Good afternoon, everyone.

大家下午好。

Chris discussed plozasiran and zodasiran at a high level, but I want to spend some time going over a few specific things.

Chris 在較高層面上討論了 plozasiran 和 zodasiran，但我想花一些時間討論一些具體的事情。

First, the data on the SHASTA-2 study it was at year end that we presented at ACC and simultaneously published in JAMA cardiology.

首先，我們在年底在 ACC 上展示了 SHASTA-2 研究的數據，並同時發表在《JAMA 心臟病學》雜誌上。

Second, the design and status of SHASTA-3, 4 and 5.

二、SHASTA-3、4、5的設計及現況。

Third, expectations for our upcoming EAS and NLA presentations.

第三，對我們即將舉行的 EAS 和 NLA 演示的期望。

And lastly, a review of the soon to report PALISADE study of plozasiran in familial chylomicronemia syndrome or FCS.

最後，對即將通報的 plozasiran 治療家族性乳糜微粒血症症候群 (FCS) 的 PALISADE 研究進行回顧。

Let's jump right in with the SHASTA-2 study of plozasiran.

讓我們直接進入 plozasiran 的 SHASTA-2 研究。

To review plozasiran is designed to reduce production of apolipoprotein C-III, or APOC3, a component of triglyceride rich lipoproteins, TRLs and a key regulator of triglyceride metabolism.

回顧一下，plozasiran 旨在減少載脂蛋白 C-III 或 APOC3 的產生，載脂蛋白 C-III 是富含三酸甘油酯的脂蛋白、TRL 的組成部分，也是三酸甘油酯代謝的關鍵調節劑。

APOC3 increases plasma triglyceride levels by inhibiting breakdown of TRL's by lipoprotein life base.

APOC3 透過抑制脂蛋白生命鹼對 TRL 的分解來增加血漿三酸甘油酯水平。

It also inhibits uptake of remnant cholesterols derived from TRL's by hepatic receptors in the liver.

它還可以抑制肝臟中的肝臟受體對源自 TRL 的殘餘膽固醇的吸收。

The SHASTA-2 study was a double-blind placebo-controlled Phase 2b study in adults with severe hypertriglyceridemia or SHTG.

SHASTA-2 研究是一項針對患有嚴重高三酸甘油酯血症或 SHTG 的成人的雙盲安慰劑對照 2b 期研究。

Three dose levels of processor at 10 milligrams, 25 milligrams and 50 milligrams were evaluated against placebo in 229 participants with fasting triglycerides of greater than or equal to 500 milligrams per deciliter at screening.

在篩選時空腹三酸甘油酯大於或等於 500 毫克/分升的 229 名參與者中，對 10 毫克、25 毫克和 50 毫克三個劑量水平的處理器與安慰劑進行了評估。

Each participant received subcutaneous injections on day one and at week 12 with subjects had followed all the way out to week 48.

每位參與者在第一天和第 12 週接受皮下注射，受試者一直追蹤到第 48 週。

The primary objective of this study was to evaluate the safety and efficacy of plozasiran in adults with SHTG to select a dosing regimen for later stage clinical studies in this patient population.

本研究的主要目的是評估 plozasiran 在成人 SHTG 中的安全性和有效性，以便為該患者群體的後期臨床研究選擇給藥方案。

SHTG is characterized by triglyceride levels greater than 500 milligrams per deciliter and is known to significantly increase the risk of ASCVD and acute pancreatitis, often with recurrent attacks requiring repeat hospital admissions and worsening outcomes.

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 ASCVD 和急性胰臟炎的風險，通常會導致反覆發作，需要重複入院並導致結局惡化。

Pancreatitis risk is proportional to the number of characteristics and concentrations of TRLs and increases as triglycerides increase.

胰臟炎的風險與 TRL 的特徵數量和濃度成正比，並隨著三酸甘油酯的增加而增加。

Currently available drug therapies generally don't sustainably reduce triglycerides below the pancreatitis risk threshold.

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胰臟炎風險閾值以下。

In addition to SHASTA-2, there is also an open label extension study that is ongoing.

除了 SHASTA-2 之外，還有一項正在進行的開放標籤擴展研究。

So final data from the double-blind treatment period of SHASTA-2 were presented at ACC and published in JAMA cardiology.

因此，SHASTA-2 雙盲治療期的最終數據在 ACC 上公佈，並發表在《JAMA 心臟病學》雜誌上。

These were exciting data which received a lot of attention and were well received at ACC and subsequent discussions with physicians.

這些令人興奮的數據受到了廣泛關注，並在 ACC 以及隨後與醫生的討論中受到好評。

With respect to pharmacologic activity, treatment with plozasiran led to dose-dependent placebo-adjusted reductions in triglycerides at 24 weeks, which was the primary endpoint.

就藥理活性而言，24 週時，plozasiran 治療導致三酸甘油酯劑量依賴性安慰劑調整降低，這是主要終點。

The reduction observed were 49%-minus, 53%-minus and 57%-minus for the 10 milligram , 25 milligram and 50 milligram doses, respectively.

對於 10 毫克、25 毫克和 50 毫克劑量，觀察到的減少量分別為 49%-、53%-和 57%-。

For perspective, currently available drugs usually would be expected to produce reductions of maybe 20% or so.

從長遠來看，目前可用的藥物通常預計可以減少 20% 左右。

As expected these triglyceride reductions were driven by corresponding placebo-adjusted reductions in APOC3 of 68%-minus, 72%-minus, 70%-minus at week 24.

正如預期的那樣，這些三酸甘油酯的降低是由第 24 週時 APOC3 相應的安慰劑調整降低 68%-、72%-、70%-推動的。

All these measures were highly statistically significant.

所有這些措施都具有高度統計顯著性。

With 24 measurements represent the point of minimal efficacy referred to as trough measurements just prior to the next planned quarterly dose.

24 次測量代表最低功效點，稱為下一個計畫季度劑量之前的谷值測量。

Mean maximum non-placebo-adjusted reductions from baseline in triglycerides at APOC3 were up to 86% and 90% respectively, and typically occurred around week 16 or week 20.

APOC3 時三酸甘油酯相對於基線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。

Importantly, we also looked at the percentage of patients who met the goal of reducing triglyceride levels below 500 milligrams per deciliter, a level above which the risk of acute pancreatitis meaningfully increases.

重要的是，我們還研究了達到將三酸甘油酯水平降低到 500 毫克/分升以下目標的患者百分比，高於該水平，急性胰臟炎的風險會顯著增加。

Among subjects treated with placebo was read at the week 24 trough time point greater than 90% receiving the 25 milligram or 50 milligram doses achieved triglyceride levels less than 500 milligrams per deciliter.

在接受安慰劑治療的受試者中，在第 24 週的谷時間點，超過 90% 接受 25 毫克或 50 毫克劑量的受試者的三酸甘油酯水平達到低於 500 毫克/分升。

In addition, around half of the subjects at these doses achieved normal triglyceride levels of less than 150 milligrams per deciliter at week 24, which is surprising given the mean starting levels of almost 900 milligrams 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/分升的正常三酸甘油酯水平，考慮到平均起始水平接近900 毫克/分升，這是令人驚訝的。

In addition to reductions in triglycerides, subjects treated with plozasiran also showed improvements in multiple atherogenic lipid 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 in SHASTA-2.

Plozasiran 在 SHASTA-2 中表現出良好的安全性。

Observed adverse events generally reflected the comorbidities and underlying conditions of the study population.

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。

The adverse event and serious adverse event profiles were generally similar across treatment groups, although worsening of diabetes did appear more frequently in the 50 milligram dose.

儘管在 50 毫克劑量中糖尿病惡化的頻率確實更高，但各治療組的不良事件和嚴重不良事件情況總體相似。

All serious treatment emergent adverse effects were deemed not related to plozasiran.

所有嚴重的治療出現的不良反應均被認為與 plozasiran 無關。

Overall, then the deep consistent and sustained reductions in APOC3 and triglycerides.

整體而言，APOC3 和三酸甘油酯持續深度降低。

An improvement in multiple atherogenic lipoprotein levels gives us a level of confidence as we initiate Phase 3 studies in patients with SHTG.

當我們在 SHTG 患者中啟動 3 期研究時，多種致動脈粥樣硬化脂蛋白水平的改善給了我們一定的信心。

These Phase 3 studies are called SHASTA-3, SHASTA-4, and SHASTA-5.

這些 3 期研究稱為 SHASTA-3、SHASTA-4 和 SHASTA-5。

I'll start with descriptions of SHASTA-3 and SHASTA-4 since they are very similar to each other and are being initiated now.

我將從 SHASTA-3 和 SHASTA-4 的描述開始，因為它們彼此非常相似並且現在正在啟動。

Both studies are global, randomized, double-blind, placebo-controlled Phase 3 studies to evaluate the efficacy and safety of Plozasiran in adult subjects with SHTG.

這兩項研究都是全球、隨機、雙盲、安慰劑對照的 3 期研究，旨在評估 Plozasiran 在患有 SHTG 的成人受試者中的有效性和安全性。

Eligible subjects will be randomized to receive either Plozasiran at 25 milligrams or placebo.

符合條件的受試者將被隨機分配接受 25 毫克 Plozasiran 或安慰劑。

In the double-blind treatment period duration will be one year, where subjects receive a total of four quarterly doses.

雙盲治療期為期一年，受試者每季總共接受四次劑量。

After month 12 eligible subjects will be offered an opportunity to continue in an optional open-label extension.

在第 12 個月後，符合條件的受試者將有機會繼續進行可選的開放標籤延期。

The primary endpoint for this study is placebo adjusted percent change in fasting triglyceride levels at month 12.

本研究的主要終點是第 12 個月時安慰劑調整的空腹三酸甘油酯水平的百分比變化。

SHASTA-3 is planned to include approximately 400 subjects and SHASTA-4 is planned to include approximately 300 subjects.

SHASTA-3 計劃包括約 400 名受試者，SHASTA-4 計劃包括約 300 名受試者。

We have begun activating sites for these studies and will activate others as quickly as possible.

我們已經開始啟動這些研究的站點，並將盡快啟動其他站點。

There are already patients in screening.

目前已經有患者正在接受篩檢。

So we expect that the first patients dosed soon.

所以我們預計第一批患者很快就會接受治療。

This has moved very rapidly, and I'm proud of the work done by all of the Arrowhead teams involved, our CRO and the investigators and institutions that are participating in the studies.

這項工作進展非常迅速，我為所有參與的 Arrowhead 團隊、我們的 CRO 以及參與研究的研究人員和機構所做的工作感到自豪。

I also want to give a quick update on SHASTA-5.

我還想快速介紹一下 SHASTA-5 的最新情況。

We are still finalizing some details about the study, but it is currently planned as a multi-center, randomized, double-blind, placebo-controlled Phase 3 study to evaluate plozasiran versus placebo in approximately 140 adult subjects with SHTG at high risk of pancreatitis.

我們仍在敲定有關該研究的一些細節，但目前計劃將其作為一項多中心、隨機、雙盲、安慰劑對照的3 期研究，以在大約140 名患有胰腺炎高風險的SHTG 成人受試者中評估plozasiran 與安慰劑的比較。

Subjects must have triglyceride levels greater than 880 milligrams per deciliter and a history of acute pancreatitis events that will be randomized in a 1:1 ratio to receive either placebo or 25 milligrams or placebo dose quarterly.

受試者的三酸甘油酯水平必須大於 880 毫克/分升，並且有急性胰臟炎事件史，受試者將以 1:1 的比例隨機接受安慰劑或每季度接受 25 毫克或安慰劑劑量。

The primary endpoint of the study is incidence of adjudicated acute pancreatitis events compared to placebo.

研究的主要終點是與安慰劑相比，判定的急性胰臟炎事件的發生率。

Now the SHASTA-3 and SHASTA-4 have been initiated to possess our strong clinical development team is finalizing the SHASTA-5 design and working to initiate the study as soon as possible.

目前SHASTA-3和SHASTA-4已啟動，我們強大的臨床開發團隊正在敲定SHASTA-5的設計，並努力盡快啟動研究。

We think performing a dedicated study in this high-risk population, if successful, will be useful for payers on a global basis.

我們認為，對這一高風險族群進行專門研究，如果成功的話，將對全球的付款人有用。

Next, I want to highlight some upcoming presentations on plozasiran and zodasiran at the European Atherosclerosis Society or EAS. on May 28 and 29, we will be presenting the final results from the MUIR study of plozasiran and the ARCHES-2 to study of zodasiran.

接下來，我想重點介紹即將在歐洲動脈粥樣硬化協會 (EAS) 上發表的有關 plozasiran 和 zodasiran 的一些演講。 5 月 28 日至 29 日，我們將展示 plozasiran 的 MUIR 研究和 zodasiran 的 ARCHES-2 研究的最終結果。

Both of these studies are a mixed type of dyslipidemia populations recruited with identical enrollment criteria.

這兩項研究都是以相同的入組標準招募的混合型血脂異常族群。

For clarity, this field is moving away from the term mixed dyslipidemia to the term mixed hyperlipidemia.

為了清楚起見，該領域正在從術語混合性血脂異常轉向術語混合性高脂血症。

So expect to see and hear the two terms used synonymously in the short term, but in the longer term, expect to hear mixed hyperlipidemia used both frequently.

因此，預計短期內會看到和聽到這兩個術語同義使用，但從長遠來看，預計會聽到混合性高脂血症頻繁使用這兩個術語。

I already described plozasiran and mechanistically, but to review, zodasiran is designed to reduce production of angiopoietin-like protein three or ANGPTL3, which like ApoC3 is a parasite expressed regulator of triglyceride metabolism.

我已經描述了 plozasiran 和機制，但回顧一下，zodasiran 旨在減少血管生成素樣蛋白 3 或 ANGPTL3 的產生，與 ApoC3 一樣，它是甘油三酯代謝的寄生蟲表達調節劑。

However, ANGPTL3 was similar to ApoC3 and having an effect on lipoprotein lipase also impacts endothelial lipase and non LDL receptor mediated uptake of LDL.

然而，ANGPTL3 與 ApoC3 相似，對脂蛋白脂肪酶有影響，也會影響內皮脂肪酶和非 LDL 受體介導的 LDL 攝取。

As such by reducing ANGPTL3, zodasiran causes some downstream changes in atherogenic lipids and lipoproteins that are different than those produced plozasiran.

因此，透過減少 ANGPTL3，zodasiran 會引起致動脈粥樣硬化脂質和脂蛋白的一些下游變化，這些變化與 plozasiran 產生的變化不同。

These include additional reductions in LDL-C and Apolipoprotein B, while also driving similar reductions in triglycerides, remnant cholesterol and non-HDL cholesterol associated with plozasiran.

這些包括額外降低 LDL-C 和載脂蛋白 B，同時也推動與 plozasiran 相關的三酸甘油酯、殘餘膽固醇和非 HDL 膽固醇類似降低。

This is why we are taking a very close look at the various options for Phase 3 clinical development in an ASCVD population with mixed hyperlipidemia, a population of patients estimated to be around $20 million in the US alone.

這就是為什麼我們正在非常仔細地研究針對患有混合性高血脂症的 ASCVD 族群進行 3 期臨床開發的各種選擇，僅在美國，該患者群體的估計價值約為 2000 萬美元。

We have engaged with external advisers and have completed exhaustive analysis of potential designs and studies.

我們與外部顧問合作，並完成了對潛在設計和研究的詳細分析。

We have recently completed a submission to the FDA on a potential study design, and we'll have additional interactions on the specifics over the coming 30 to 60 days.

我們最近完成了向 FDA 提交的一項潛在研究設計的提交，我們將在未來 30 到 60 天內就具體細節進行更多互動。

We will talk more about our plans after we receive feedback from FDA and other key agencies.

在收到 FDA 和其他主要機構的回饋後，我們將更多地討論我們的計劃。

Upstream of that, the coming EAS presentations will be a good way for folks outside the company to see some of the data that have gone into our thinking.

除此之外，即將舉行的 EAS 演示將是公司外部人員了解我們思考的一些數據的好方法。

We and our KOL advisors believe that there really is not a bad choice between the two as you will see results from both near and are just to look compelling.

我們和我們的 KOL 顧問相信，兩者之間確實沒有一個糟糕的選擇，因為您會看到兩者的結果很接近，而且看起來很引人注目。

Now moving to the PALISADE study of plozasiran in patients with FCS, PALISADE included FCS patients who are genetically confirmed and somewhere around half who are clinically diagnosed.

現在轉向針對 FCS 患者進行 plozasiran 的 PALISADE 研究，PALISADE 納入了基因確診的 FCS 患者以及大約一半的臨床診斷患者。

FCS is a severe and ultra rare genetic condition often caused by various monogenic mutations.

FCS 是一種嚴重且極為罕見的遺傳疾病，通常由各種單基因突變引起。

FCS leads to extremely high triglyceride levels which can lead to various serious signs and symptoms, most notably including acute and potentially fatal pancreatitis.

FCS 會導致三酸甘油酯水平極高，從而導致各種嚴重的體徵和症狀，最明顯的是包括急性和可能致命的胰臟炎。

Currently, the available therapeutic options lead most FCS patients persistently vulnerable to pancreatitis.

目前，現有的治療選擇導致大多數 FCS 患者持續容易罹患胰臟炎。

The PALISADE study is a Phase 3 placebo-controlled study to evaluate the efficacy and safety of plozasiran in adults with FCS.

PALISADE 研究是一項 3 期安慰劑對照研究，旨在評估 plozasiran 對成人 FCS 的療效和安全性。

The primary endpoint of the study is percent change from baseline in fasting triglycerides at month 10, a total of 75 subjects were randomized to receive 25 milligrams of plozasiran, 50 milligrams plozasiran and or matching placebo once every three months.

研究的主要終點是第10 個月時空腹甘油三酯相對於基線的變化百分比，共有75 名受試者被隨機分配，每三個月接受一次25 毫克plozasiran、50 毫克plozasiran 和/或匹配的安慰劑。

Participants who completed the randomized period are eligible to continue in two parts extension period were all participants are receiving plozasiran.

如果所有參與者都接受 plozasiran，則完成隨機期限的參與者有資格繼續分成兩部分延長期間。

The last study visit for the last patient enrolled in PALISADE occurred about a week ago.

最後一位參加 PALISADE 的患者的最後一次研究訪視發生在大約一周前。

This will be Arrowhead's first, completed Phase 3 study and represents a significant milestone for the company.

這將是 Arrowhead 首次完成的第三階段研究，代表著該公司的一個重要里程碑。

Importantly, it brings plozasiran potentially closer to the FCS patients that may benefit.

重要的是，它使 plozasiran 可能更接近可能受益的 FCS 患者。

Our goal now is to work efficiently to generate initial study results and provide a top-line data readout as soon as our cardiometabolic webinar next month and subsequently present a fuller dataset at an appropriate medical meeting.

我們現在的目標是有效地工作，產生初步研究結果，並在下個月的心臟代謝網絡研討會上提供最重要的數據讀數，並隨後在適當的醫學會議上提供更完整的數據集。

This is an exciting time at Arrowhead as we eagerly await these results.

這是 Arrowhead 激動人心的時刻，我們熱切地等待這些結果。

I'll now turn the call over to Jacques.

我現在將電話轉給雅克。

Thank you, Bruce.

謝謝你，布魯斯。

The discovery and early development teams made some notable progress over the last quarter, and we also have a busy several months ahead with the summer series of R&D webinars that Chris mentioned earlier.

發現和早期開發團隊在上個季度取得了一些顯著進展，克里斯之前提到的夏季系列研發網路研討會也將在未來幾個月讓我們忙碌起來。

We do an enormous amount of work and seeking to innovate new medicines.

我們做了大量的工作並尋求創新藥物。

That is often only recognized once there is a clinical candidate.

這通常只有在出現臨床候選人後才會被認可。

So I wanted to talk for a moment about how we see our priorities and the goals of the team.

所以我想談談我們如何看待我們的優先事項和團隊的目標。

Number one is to push the TRiM platform to new cell types and continually seek to optimize the safety and activity of each construct.

第一個是將 TRiM 平台推向新的細胞類型，並不斷尋求優化每種構建體的安全性和活性。

Number two is to develop new candidates against attractive gene targets for using RNA interference to the only or best method to inhibit the target.

第二是開發針對有吸引力的基因標靶的新候選藥物，以使用 RNA 幹擾來抑制標靶的唯一或最佳方法。

Number three is to conduct IND-enabling nonclinical studies and first-in-human clinical studies in the most efficient manner possible to get meaningful readouts that accelerate mid and late-stage development.

第三是以最有效的方式進行支持 IND 的非臨床研究和首次人體臨床研究，以獲得有意義的讀數，從而加速中後期開發。

And number four is to develop assets, which can be readily partnered and support business development activities, which remains a key strategic focus as our pipeline has continued to grow.

第四是開發可以輕鬆合作並支援業務開發活動的資產，隨著我們的管道不斷成長，這仍然是一個關鍵的策略重點。

I think we've made good strides in these areas recently.

我認為我們最近在這些領域取得了很大進展。

So let's talk about a few examples.

那麼讓我們來談談幾個例子。

We've continued to expand the reach of the TRiM platform.

我們不斷擴大 TRiM 平台的覆蓋範圍。

We now have clinical programs in three different tissue types including liver, lung and muscle.

我們現在有針對三種不同組織類型的臨床項目，包括肝臟、肺部和肌肉。

We also expect in the very near future to have clinical programs in two additional tissues, specifically CNS and adipose.

我們也期望在不久的將來在另外兩種組織中開展臨床項目，特別是中樞神經系統和脂肪。

Each one of these expands the universe of diseases we can address and the number of patients that we can potentially help.

其中每一項都擴大了我們可以解決的疾病範圍以及我們可以幫助的患者數量。

During the CNS R&D webinar scheduled for September, we plan on giving an update on a specific candidate that is currently undisclosed and highlight the significant progress we're making on a subcutaneously administered construct designed to deliver siRNA across the blood-brain barrier to the CNS without the need for intrathecal administration.

在定於9 月舉行的中樞神經系統研發網路研討會期間，我們計劃提供目前尚未公開的特定候選藥物的最新情況，並強調我們在皮下注射構建體方面取得的重大進展，該構建體旨在將siRNA 穿過血腦屏障傳遞至中樞神經系統無需鞘內給藥。

This is a much more patient friendly mode of administration and may be able to access tissues in the deep brain that have been difficult to access with IT injections.

這是一種對患者更友善的給藥方式，並且可能能夠進入大腦深處的組織，而這些組織是透過 IT 注射難以進入的。

This is potentially a big step forward for us in the field overall, and we are excited about the progress.

這對我們整個領域來說可能是一大進步，我們對這項進展感到興奮。

During the obesity and metabolic R&D webinars currently scheduled for August.

目前定於八月舉行的肥胖和代謝研發網路研討會。

We will also talk about platform advancements and pipeline expansion.

我們還將討論平台進步和管道擴展。

The pipeline is expanding by two programs and we will talk about the addition of adipocytes as a new cell type we can access with the TRiM platform.

該管道正在透過兩個項目進行擴展，我們將討論添加脂肪細胞作為我們可以透過 TRiM 平台存取的新細胞類型。

As you all know, the obesity space has recently gained a lot of attention with the success of GLP-1 agents.

眾所周知，隨著 GLP-1 藥物的成功，肥胖領域最近引起了廣泛關注。

However, we see clear areas that remain underserved.

然而，我們看到明顯的領域仍然服務不足。

We have not disclosed much publicly about the development of our two obesity programs.

我們還沒有公開透露太多關於我們兩個肥胖計畫的進展。

So this event will be a good opportunity to get people up to speed on where we are and where we see the clinical development programs going.

因此，這次活動將是一個很好的機會，讓人們了解我們的現狀以及我們對臨床開發專案的進展。

Moving on to current clinical development programs during the last quarter, we brought two new agents into the clinic.

在上個季度繼續目前的臨床開發計劃，我們將兩種新藥物引入臨床。

First, ARO-CFB is designed to reduce hepatic expression of complement factor B, which plays an important regulatory role and amplifying complement alternative pathway activation and has been identified as a promising therapeutic target.

首先，ARO-CFB旨在減少補體因子B的肝臟表達，補體因子B發揮重要的調節作用並放大補體旁路途徑的激活，並已被確定為有前途的治療標靶。

Our CFB is being developed as a potential treatment for complement mediated kidney diseases such as IGA nephropathy, which is the most common glomerular disease worldwide and carries a higher lifetime risk of progression to end-stage renal disease.

我們的 CFB 正在開發作為補體介導的腎臟疾病（例如 IGA 腎病）的潛在治療方法，IGA 腎病是世界範圍內最常見的腎小球疾病，並且具有較高的終生進展為終末期腎病的風險。

Additionally, ARO-CFB may have clinical applications in non-renal diseases involving complement activation.

此外，ARO-CFB 可能在涉及補體活化的非腎臟疾病中具有臨床應用。

Last month, we announced that we had dosed the first subjects in a Phase 1/2a clinical trial of ARO-CFB designed to enroll up to 66 healthy volunteers and patients with complement-mediated kidney disease.

上個月，我們宣布已經對ARO-CFB 1/2a 期臨床試驗的第一批受試者進行了給藥，該試驗旨在招募多達66 名健康志願者和患有補體介導的腎臟疾病的患者。

Second, new clinical program, ARO-DM1 is designed to reduce expression of the dystrophy and myotonic of protein kinase or DMPK gene in the muscle as a potential treatment for patients with Type one myotonic dystrophy or DM1.

其次，新的臨床計畫ARO-DM1旨在減少肌肉中蛋白激酶或DMPK基因的營養不良和強直性表達，作為一型強直性肌肉營養不良或DM1患者的潛在治療方法。

Pathogenesis of DM1 is driven by abnormal DMPK transcripts that cause misregulated splicing, known as place apathy for certain messenger RNAs, which are directly linked to the clinical manifestations of DM1.

DM1 的發病機制是由異常 DMPK 轉錄物驅動的，異常的 DMPK 轉錄物會導致剪接失調，即對某些信使 RNA 的位置冷漠，這與 DM1 的臨床表現直接相關。

In March, we announced that we had initiated and dosed the first subjects in a Phase 1 to a double blinded placebo-controlled dose escalating study to evaluate single and multiple ascending doses of ARO-DM1 in up to the 48 subjects with DM1.

今年3 月，我們宣布，我們已啟動一項雙盲安慰劑對照劑量遞增研究，並對第一階段的第一批受試者進行給藥，以評估最多48 名DM1 受試者的單次和多次遞增劑量的ARO-DM1。

Moving on to our clinical stage pulmonary programs, ARO-RAGE, AROMUC5AC, and ARO-MMP7.

繼續我們的臨床階段肺部計畫 ARO-RAGE、AROMUC5AC 和 ARO-MMP7。

We continued to enroll patients across all three programs and are confident that we will have multiple opportunities for clinical readouts this year.

我們繼續在所有三個項目中招募患者，並相信今年我們將有多次臨床讀數的機會。

The first of these will occur at ATS later this month.

第一個項目將於本月晚些時候在 ATS 上進行。

We are scheduled to present a poster on ARO-RAGE, which will include data from mild to moderate asthma patient cohorts that we have not reported on previously.

我們計劃展示 ARO-RAGE 的海報，其中將包括我們之前未報導的輕度至中度氣喘患者群組的數據。

To review ARO-RAGE designed to reduce expression of the receptor for advanced application end products or RAGE as a potential treatment for inflammatory pulmonary diseases.

回顧 ARO-RAGE 旨在減少受體表達的高級應用最終產品或 RAGE 作為發炎性肺部疾病的潛在治療方法。

We are currently enrolling asthma patients with high baseline levels of fractional exhaled nitric oxide or FeNO which is a biomarker of IL-13 driven type two inflammation in the lung.

我們目前正在招募呼出一氧化氮分數或 FeNO 基線水平較高的氣喘患者，FeNO 是 IL-13 驅動的肺部二型發炎的生物標記。

We are expecting to have high FeNO cohorts enrolled and dosed late this year.

我們預計今年稍後將有高 FeNO 團隊列入組並接受給藥。

The next programs are ARO-MUC5AC, which is designed to reduce production of mucin 5AC, or MUC5AC as a potential treatment for muco-obstructive pulmonary diseases and ARO-MMP7, which is designed to reduce the expression of Matrix metalloproteinase 7 or an MMP7 as a potential treatment for idiopathic pulmonary fibrosis or IPF.

下一個計劃是ARO-MUC5AC，旨在減少粘蛋白5AC 或MUC5AC 的產生，作為粘液阻塞性肺部疾病的潛在治療方法；ARO-MMP7，旨在減少基質金屬蛋白酶7 或MMP7 的表達，作為粘液阻塞性肺部疾病的潛在治療方法。

Both ARO-MUC5AC and ARO-MMP7 have already enrolled and dosed healthy volunteers, and we anticipate the patient cohorts will be enrolled and dosed in time to enable initial clinical readouts in the second half of this year.

ARO-MUC5AC 和 ARO-MMP7 都已經招募了健康志願者並對其進行了給藥，我們預計患者隊列將及時進行招募和給藥，以便在今年下半年實現初步臨床讀數。

Our pulmonary R&D webinar scheduled for July will review these programs in more detail.

我們定於 7 月舉行的肺部研發網路研討會將更詳細地回顧這些項目。

I will now turn the call over to Ken.

我現在會把電話轉給肯。

Thank you, James, and good afternoon, everyone.

謝謝詹姆斯，大家下午好。

As we reported today, our net loss for the quarter ended March 31, 2024 was $125.3 million or $1.2 per share based on a 123.3 million fully diluted weighted average shares outstanding.

正如我們今天報導的那樣，截至 2024 年 3 月 31 日的季度淨虧損為 1.253 億美元，即每股 1.2 美元，基於 1.233 億股完全稀釋加權平均流通股計算。

This compares with net income of $48.7 million or $0.45 per share based on 108.1 million fully diluted weighted average shares outstanding for the quarter ended March 31, 2023.

相比之下，根據截至 2023 年 3 月 31 日的季度的 1.081 億股完全稀釋加權平均流通股計算，淨利潤為 4,870 萬美元，即每股 0.45 美元。

No revenue was recorded in the quarter and in the quarter ended March 31, 2024, revenue of $146.3 million was recorded in the quarter ended March 31, 2023.

該季度沒有記錄收入，截至 2024 年 3 月 31 日的季度，截至 2023 年 3 月 31 日的季度記錄了 1.463 億美元的收入。

Revenues recognized as we complete our performance obligations or key developmental milestones are reached.

當我們完成履約義務或達到關鍵發展里程碑時確認收入。

Revenue in the prior period, primarily related to the recognition of payments received from our license and collaboration agreements with Takeda and GSK.

上期收入主要與確認從我們與武田和葛蘭素史克的許可和合作協議中收到的付款有關。

Total operating expenses for the quarter ended March 31, 2024 were $126.2 million compared to $98.1 million for the quarter ended March 31, 2023.

截至 2024 年 3 月 31 日的季度的總營運費用為 1.262 億美元，而截至 2023 年 3 月 31 日的季度的總營運費用為 9,810 萬美元。

The key drivers of this change were increased research and development costs, primarily compensation cost and candidate costs as the company's pipeline of clinical candidates has increased and advanced to into later stages of development.

這項變化的主要驅動因素是研發成本增加，主要是補償成本和候選成本，因為公司的臨床候選產品管道已經增加並進入後期開發階段。

Net cash used in operating activities during the quarter ended March 31, 2024 was $92.4 million compared to with $31.7 million during the quarter ended March 31, 2023.

截至 2024 年 3 月 31 日的季度營運活動使用的現金淨額為 9,240 萬美元，而截至 2023 年 3 月 31 日的季度為 3,170 萬美元。

The increase in cash used in operating activities was primarily driven by higher R&D expenses as well as the prior period, including $40 million cash receipt of revenue milestones.

經營活動所用現金的增加主要是由於研發費用以及上一時期的增加所致，其中包括收入里程碑的 4,000 萬美元現金收入。

Construction of our Veronate facility is effectively complete.

我們的維羅納特工廠的建設已有效完成。

We are currently undertaking commissioning and qualification activities, which puts us on track for manufacturing drug material to support our clinical trials later this year.

我們目前正在進行調試和資格認證活動，這使我們能夠生產藥物材料以支援今年稍後的臨床試驗。

We expect final payments to be made over the next several months, totaling $50 million, after which we expect capital expenditures to be nominal.

我們預計最終付款將在未來幾個月內支付，總額為 5000 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 $523.1 million at March 31, 2024 compared to $403.6 million at September 30, 2023.

轉向我們的資產負債表，截至 2024 年 3 月 31 日，我們的現金和投資總額為 5.231 億美元，而 2023 年 9 月 30 日為 4.036 億美元。

The increase in our -- cash and investments was primarily related to the $450 million equity issuance, partially offset by our ongoing cash burn.

我們的現金和投資的增加主要與 4.5 億美元的股票發行有關，部分被我們持續的現金消耗所抵銷。

Our common shares outstanding at March 31, 2024 were $124.1 million.

截至 2024 年 3 月 31 日，我們已發行的普通股為 1.241 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 again.

再次感謝。

This has been another quarter of solid execution for Arrowhead.

這是 Arrowhead 執行力強勁的另一個季度。

Our Phase 3 PALISADE study of plozasiran clinically complete, which sets us up to take the next step in growth for Arrowhead as we make the transition into a commercial organization provided we receive regulatory approval.

我們對 plozasiran 的 3 期 PALISADE 研究已臨床完成，這使我們能夠在獲得監管部門批准的情況下，在向商業組織轉型時為 Arrowhead 邁出下一步的發展。

We also initiated the SHASTA-3, and SHASTA-4 Phase 3 studies of plozasiran in patients with SHTG and finalizing the design and preparations to initiate SHASTA-5 in patients with SHTG at high risk of acute pancreatitis.

我們也啟動了 plozasiran 在 SHTG 患者中的 SHASTA-3 和 SHASTA-4 3 期研究，並最終確定了在急性胰臟炎高風險 SHTG 患者中啟動 SHASTA-5 的設計和準備工作。

We are waiting for FDA feedback on the Phase 3 program to address ASCVD, which we will discuss after we reach regulatory alignment.

我們正在等待 FDA 對解決 ASCVD 的第 3 階段計劃的反饋，我們將在達成監管一致後進行討論。

In addition to progress in cardiometabolic, we have been very productive in platform development and pipeline expansion.

除了在心臟代謝方面取得進展外，我們在平台開發和產品線擴展方面也取得了非常豐碩的成果。

Our TRiM platform can now deliver to CNS and adipose tissue, and we will soon have new clinical programs targeting those tissues.

我們的 TRiM 平台現在可以輸送到中樞神經系統和脂肪組織，我們很快就會有針對這些組織的新臨床計畫。

We also initiated clinical studies during the quarter for two new candidates,ARO-DM1 and ARO-CFB.

我們也在本季啟動了兩種新候選藥物 ARO-DM1 和 ARO-CFB 的臨床研究。

Thank you for joining us today, and I'd now like to open the call to your questions.

感謝您今天加入我們，現在我想開始回答您的問題。

Operator?

操作員？

Thank you.

謝謝。

At this time, we will conduct the question-and-answers.

這時候我們就進行問答。

(Operator Instructions)

（操作員說明）

Luca Issi, RBC Capital.

盧卡·伊西，加拿大皇家銀行資本。

Thanks so much for taking the question.

非常感謝您提出問題。

Congrats on the progress.

祝賀取得的進展。

Maybe FeNO, sounds like the high FeNO cohorts will RAGE has been slow to enroll.

也許 FeNO，聽起來高 FeNO 群體會 RAGE 的註冊速度很慢。

Can you maybe just expand on it?

您可以擴充一下嗎？

When is the earliest we can actually see that data and maybe what are the bogies in term of FeNO reduction that are below on par or above your expectations?

我們最早什麼時候才能真正看到這些數據，也許在 FeNO 減少方面低於或高於您的預期的轉向架是什麼？

And then maybe second on LPLA, what was your reaction to really start a cardiovascular outcome trial that is way bigger than your trial than Novartis's trial?

然後也許關於 LPLA 的第二個問題，您對真正開始一項比您的試驗比諾華的試驗規模大得多的心血管結果試驗有何反應？

I think Novartis has a 7,000 patient trial.

我認為諾華有一個 7,000 名患者的試驗。

You have an 8,000 patient trial versus Lilly starting at 30,000 patient trial here for LPLA.

您對 LPLA 進行了 8,000 名患者的試驗，與禮來公司的試​​驗從 30,000 名患者開始。

Does that mean that your trial is underpowered?

這是否意味著你的審判能力不足？

Any thoughts there much appreciated.

任何想法都非常感激。

Thanks so much.

非常感謝。

I think, look, I can address FeNO question.

我想，聽著，我可以解決 FeNO 的問題。

It's look, it's just been slow to enroll because we are requiring high FeNO in these patients with moderate to severe asthma.

看起來，招募速度很慢，因為我們對這些中度至重度氣喘患者需要高 FeNO。

So that I don't have good visibility on when that could be complete.

所以我不太清楚什麼時候可以完成。

I think our take-home message there was that we were signaling around.

我認為我們的主要訊息是我們正在發出信號。

We think this is a good drug and we want to move and expeditiously into a Phase 2.

我們認為這是一種好藥，我們希望迅速進入第二階段。

And so we're going, we've got a Phase 2 design and we are moving towards that.

所以我們已經有了第二階段的設計，我們正在朝著這個方向前進。

I think we'll start that in the fourth quarter.

我想我們會在第四季開始。

And so we are looking forward to seeing that FeNO data, of course, but it's not rate limiting.

當然，我們期待看到 FeNO 數據，但這不是速率限制。

I think the drug is too important to wait for that.

我認為藥物太重要了，不能等。

Bruce, you have anything to add about the LPLA?

Bruce，您對 LPLA 有什麼要補充的嗎？

I don't think there's a problem with the Novartis or Amgen study is being underpowered.

我不認為諾華或安進的研究有動力不足的問題。

I don't really know what's driving that very large study size for [Eli Lilly], they're the devil may be in the details there, but I don't worry about the power of either the Novartis or the Amgen studies.

我真的不知道是什麼推動了禮來公司如此大規模的研究，他們的問題可能在於細節，但我不擔心諾華或安進研究的力量。

Edward Tenthoff, Piper Sandler.

愛德華·騰索夫，派珀·桑德勒。

Great. Thank you very much.

偉大的。非常感謝。

So many things going on tough to the side where to start.

很多事情都很難從哪裡開始。

But with a Phase 3 PALISADE data coming up top line data to cardiovascular events, again, what kind of expectations should we look for in the trig lowering from especially with data already out, from the earlier studies?

但是，隨著第 3 期 PALISADE 數據出現在心血管事件的第一線數據中，我們應該對三角函數降低有何期望，尤其是在早期研究中已經公佈的數據的情況下？

And how will this really compare?

這真的會如何比較呢？

Do you think with the program, which is a little bit ahead of you guys.

你認為這個程式有點超前你們嗎？

How do you expect to compete for the small patient population?

您預計如何爭奪少量患者群體？

Thanks,.

謝謝，。

Well, as far as expectations go, that's the hit you're asking me for a crystal ball.

好吧，就期望而言，這就是你向我要水晶球的打擊。

But yes, I think that all our indications so far is that plozasiran, it's a very powerful drug when it comes to knocking down APOC3 and APOC3 seems to be very important for this patient population.

但是，是的，我認為到目前為止我們所有的跡像都是 plozasiran，它是一種非常強大的藥物，可以抑制 APOC3，並且 APOC3 似乎對這個患者群體非常重要。

But that said, I mean, I don't have any insight into your at this point.

但話雖如此，我的意思是，我目前對你還沒有任何了解。

What that's the PALISADE data will show, so hopes or hopes.

PALISADE 數據將顯示什麼，所以希望或希望。

But in reality, you guys see the data.

但實際上，你們看到的是數據。

That said I don't have any reason to believe that that we won't expect a good outcome.

也就是說，我沒有任何理由相信我們不會期待有一個好的結果。

But these trials are the 75 patient trial.

但這些試驗是75名患者的試驗。

So we'll have to see how the trial goes, how the placebo group has performed because that often times has a lot to do with happens what happens in these trials.

因此，我們必須看看試驗進行得如何，安慰劑組的表現如何，因為這通常與這些試驗中發生的情況有很大關係。

So I can't really give you a forecast on that, Ted.

所以我真的無法給你一個預測，泰德。

I mean, we're excited to see the

我的意思是，我們很高興看到

---.

---。

Just to kind of clarify, Bruce, on since to touch on off, but just to clarify?

只是為了澄清一下，布魯斯，從開始就開始，但只是為了澄清？

Go ahead.

前進。

With kind of the reductions that you've seen with the prior trig reductions in other studies and with severe hypercholesterolemia patients, et cetera, or a hypertriglyceridemia patients.

您在其他研究中以及嚴重高膽固醇血症患者等或高三酸甘油脂血症患者中看到了先前的三角肌減少。

Where do you think how do you think that will play in these FCS patients?

您認為這對這些 FCS 患者有何影響？

Sorry, that was more my question.

抱歉，這更多是我的問題。

I guess, what I can say is we've had a smattering of FCS patients.

我想，我能說的是我們有少數 FCS 患者。

And in the SHTG study.

在 SHTG 研究中。

We've had a few patients in Phase 1.

我們在第一階段有一些患者。

So far in that small number of patients, we've seen essentially similar results from the perspective of percent reductions in triglycerides between the FCS patients and for instance what we saw in the regular SHTG patients.

到目前為止，在少數患者中，從三酸甘油酯降低百分比的角度來看，FCS 患者與我們在常規 SHTG 患者中看到的結果基本上相似。

And if that holds in this larger patient population, we should be in good shape.

如果這種情況適用於更多的患者群體，那麼我們應該處於良好的狀態。

But as I said, each clinical study has its own clinical study, but we don't have reason from what we've seen so far to go in expecting a different result.

但正如我所說，每項臨床研究都有自己的臨床研究，但從迄今為止所看到的情況來看，我們沒有理由期待不同的結果。

But, we'll have a much larger patient population here to look at.

但是，我們將有更多的患者群體可供觀察。

And again, how do you guys expect that's helpful.

再說一次，你們覺得這有什麼幫助。

How do you guys expect to compete with Ionis who's a little further ahead?

你們預計如何與領先一點的 Ionis 競爭？

Thank you.

謝謝。

Yes, of course, that's going to depend upon our data.

是的，當然，這將取決於我們的數據。

Here's what I believe that we will have an advantage in dosing intervals and I think we'll be dosing once a quarter rather than once a month.

我相信我們在給藥間隔方面將具有優勢，我認為我們將每季給藥一次，而不是每月一次。

And then as Bruce says, we'll see if the data holds up with what we've seen in the past.

然後，正如布魯斯所說，我們將看看這些數據是否與我們過去所看到的數據相符。

My hope is that we continue to have a way a more powerful drug that is better tolerated, but we'll have to wait to see what the data look like in this in this relatively small study.

我希望我們能夠繼續找到一種更強大、耐受性更好的藥物，但我們必須等待，看看這項相對較小的研究中的數據是什麼樣的。

I'll also say one more thing.

我還要說一件事。

You mentioned a very small population of FCS, TED and of course, genetic FCS is not a very large population, but the population that we studied was genetic FCS and phenotypic FCS, if you will.

你提到了一個非常小的FCS群體，TED，當然，遺傳性FCS並不是一個很大的群體，但如果你願意的話，我們研究的群體是遺傳性FCS和表型FCS。

So those patients with trigs above 880 in the history of pancreatitis, and it turned that would be about half and half of our study.

因此，那些在胰臟炎病史中 trig 高於 880 的患者，結果大約占我們研究的一半。

And so we'll see what makes it to the label.

所以我們來看看是什麼讓它出現在這個標籤上的。

But that's the population that we studied, and that is a substantially larger population than simply genetic FCS.

但這就是我們研究的群體，而且這個群體比單純的遺傳 FCS 的群體大得多。

Ellie Merle of UBS.

瑞銀集團的埃莉·梅爾。

This is Jasmine on for Ellie. you being so much for taking our question.

這是艾莉的茉莉花。你非常願意回答我們的問題。

So when we get updates from patient cohorts from MUC5AC and MMP7 later in the year, can you give any color on the number of patients that we might see?

因此，當我們在今年稍後從 MUC5AC 和 MMP7 的患者群組中獲得更新時，您能否給出我們可能看到的患者數量的任何顏色？

And anything on specifically what end points we will get?

具體來說我們會得到什麼終點？

Thank you.

謝謝。

Sure.

當然。

So the number of patients it depends on enrollment we're doing -- seven per cohort in the IPF patient cohort.

因此，患者數量取決於我們正在進行的登記——IPF 患者群組中每個隊列有 7 名患者。

So but single digit number of patients call it less than 10, assuming we report, maybe the first dose of IPF patients and then the endpoint to that would be MUC5AC MMP7 levels in the balance that will measure in all IPF patients.

因此，假設我們報告，可能是 IPF 患者的第一劑劑量，那麼個位數的患者稱其少於 10，然後終點將是在所有 IPF 患者中測量的天平中的 MUC5AC MMP7 水平。

And then for MUC5AC, we probably have a little bit more in terms of number of patients, 20 or so that we have available to report on and that would be MUC5AC protein levels from a sputum.

然後對於 MUC5AC，我們可能有更多的患者數量，大約 20 名左右，我們可以報告，這將是痰中的 MUC5AC 蛋白質水平。

That's the primary biomarkers that we're looking at.

這是我們正在研究的主要生物標記。

Okay, great.

好的，太好了。

And just a quick follow-up If I could. at ATS on RAGE, can you give any specifics on what we can expect there?

如果可以的話，請快速跟進。在 RAGE 上的 ATS，您能具體說明一下我們在那裡可以期待什麼嗎？

Any data?

有數據嗎？

I mean, sure.

我的意思是，當然。

We'll be presenting the healthy volunteer RAGE data and then the RAGE, the serum RAGE knockdown data in the patient cohorts that we have available.

我們將展示健康志願者的 RAGE 數據，然後是我們現有的患者群組中的 RAGE、血清 RAGE 敲低數據。

Jason Gerberry, Bank of America.

傑森‧格伯里，美國銀行。

Hi, good evening.

嗨，晚上好。

This is Dan on for Jason.

這是丹為傑森代言。

Congrats on the progress this quarter, and thank you so much for taking our question.

恭喜本季取得的進展，非常感謝您提出我們的問題。

I just had a quick one on plozasiran.

我剛剛在 plozasiran 上快速吃了一餐。

And just in terms of thinking about the PALISADE data.

就 PALISADE 數據而言。

I believe your data will include FCS patients and high TG patients with functional LPL activity.

我相信您的數據將包括 FCS 患者和具有功能性 LPL 活性的高 TG 患者。

I'm just curious how you see the inclusion of the patients with the LPL activity, enriching your dataset and do you plan to break out clinical activity of these two subgroups to maybe inform comparisons with Ionis

我只是好奇您如何看待將具有 LPL 活動的患者納入其中，豐富您的數據集，以及您是否計劃分解這兩個亞組的臨床活動，以便與 Ionis 進行比較

[Larson].

[拉森]。

Thank you.

謝謝。

Well, as Chris said, it means that the patients that are not genetically proven FCS at the point they enroll are phenotypically FCS patients.

嗯，正如 Chris 所說，這意味著在入組時未經過基因證明 FCS 的患者是表型 FCS 患者。

So they're not just high triglyceride patients or their patients really look and feel like FCS, but they just have not had the genetics done at the time of enrollment.

因此，他們不僅僅是高三酸甘油酯患者，或者他們的患者看起來和感覺起來確實像 FCS，但他們只是在入組時沒有進行遺傳學檢查。

And as Chris said, that's a fairly large population and they tend to be, some of them are undiagnosed FCS patients, but oftentimes, they're compound heterozygous and which may or may not include LPL, but then have other genetic abnormalities as well.

正如克里斯所說，這是一個相當大的群體，他們往往是，其中一些是未確診的 FCS 患者，但通常，他們是複合雜合子，可能包括或不包括 LPL，但也有其他遺傳異常。

And the compound effect winds up having and phenotypically look like they have SCS.

複合效應最終導致它們在表型上看起來像是患有 SCS。

So it's a heterogeneous group.

所以這是一個異質群體。

And at this point, again, when we haven't seen the data, everything is blinded, can't really say how that might play into the results that's going to be one of the really interesting things to see in the data is do the genetic FCS patients will look and behave the same.

在這一點上，再次，當我們還沒有看到數據時，一切都是盲目的，無法真正說出這將如何影響結果，這將是數據中真正有趣的事情之一遺傳性FCS 患者的外表和行為都一樣。

We'll see, we'll know more once we have all the data in our hands.

我們會看到，一旦我們掌握了所有數據，我們就會了解更多。

Thank you.

謝謝。

I have a quick follow-up.

我有一個快速跟進。

Apologies, if I missed this in your prepared remarks.

抱歉，如果我在您準備好的發言中漏掉了這一點。

But to the ARO-RAGE Phase 2 asthma trial that you're planning to initiate later this year, is that an all-comers population?

但對於您計劃在今年稍後啟動的 ARO-RAGE 2 期哮喘試驗來說，這是一個所有人都參與的人群嗎？

Or is that going to the in just the eosinophilic high-type 2 patients?

或者說這僅適用於嗜酸性粒細胞高 2 型患者？

Thank you.

謝謝。

Yes, we're still waiting on feedback from the regulatory agencies.

是的，我們仍在等待監管機構的回饋。

So we'll talk more about the design later once it's clear to us.

因此，一旦我們清楚了設計，我們將在稍後討論更多。

Maury Raycroft, Jefferies.

莫里‧雷克羅夫特，傑弗里斯。

Hi, congrats on the progress and thanks for taking my question.

您好，祝賀您的進展，並感謝您提出我的問題。

And I'm going to ask one on FCS to follow-up, some of the others, assuming the genetic and clinical patients perform the same and the PALISADE FCS study, and that's very successful.

我將要求 FCS 方面的一位人員以及其他一些人員進行跟進，假設遺傳和臨床患者執行相同的操作，並且 PALISADE FCS 研究非常成功。

What are your expectations for a label?

您對標籤有什麼期望？

What the label would look like?

標籤會是什麼樣子？

And how could that play into the commercial opportunity?

這如何發揮商業機會？

And then as a follow-up, can you comment on baseline pancreatitis in this study?

作為後續行動，您能否評論一下本研究中的基線胰臟炎？

What do you expect to see on that measure.

您希望在該指標上看到什麼？

Okay.

好的。

But let me take the pancreatitis question first.

但讓我先回答胰臟炎問題。

There was a significant history of pancreatitis in the patient population, and we have had some events.

患者群體中有重要的胰臟炎病史，我們也發生過一些事件。

There's still a few events to be adjudicated that are, I think, are being adjudicated maybe this week or next.

我認為，還有一些事件需要裁決，可能會在本週或下週進行裁決。

So I don't know what the total number of pancreatitis events in the study will be in the end.

所以我不知道該研究中的胰臟炎事件總數最終會是多少。

But it's a number.

但這是一個數字。

It's hard to know enough that you will be able to hopefully see something, but we don't know at this point.

很難知道足夠的資訊來讓你有希望看到一些東西，但我們目前還不知道。

And so that's on pancreatitis.

這就是胰臟炎。

With respect to labeling, of course, we don't make that decision, the agency does.

當然，就標籤而言，我們不會做出決定，而是該機構做出決定。

But the decision to look at either genetic FCS patients or if you will, phenotypic FCS patients is something that the agency bought into.

但是，該機構決定要么研究遺傳性 FCS 患者，要么研究表型 FCS 患者。

It certainly historically when there's been agreement between the agency and a company historically, that agency tends to give you some deal labeling that reflects the population that you studied.

當然，從歷史上看，當該機構和一家公司之間達成協議時，該機構往往會給您一些反映您所研究人群的交易標籤。

Obviously, any individual situation can vary.

顯然，任何個人情況都可能有所不同。

But our certainly expectation going in would be that the labeling would reflect the patient population we studied.

但我們當然期望標籤能反映我們研究的患者群體。

And that would have an impact obviously of with respect to potentially a different, there could be a differential label between us and plozasiran.

這顯然會產生影響，因為我們和 plozasiran 之間可能存在不同的標籤。

We won't know until we get there, but we could see a distinction.

直到我們到達那裡我們才會知道，但我們可以看到一個差異。

That's really helpful.

這真的很有幫助。

And maybe one last follow-up for a number of patients out there that would be clinically defined with FCS.

也許是對許多患者的最後一次隨訪，這些患者將透過 FCS 進行臨床定義。

Do you guys have any bookends on that, what that could look like it?

你們有這方面的書擋嗎？

So we've gone at that by from a number of ways, and we feel it's in the thousands we haven't set on it on it on an exact number, but it feels like it's in the thousands beyond that.

因此，我們透過多種方式解決了這個問題，我們覺得它有數千個，我們還沒有設定一個確切的數字，但感覺它有數千個。

It's hard to tell at this point.

目前還很難說。

Mike Montani, B. Riley.

麥克·蒙塔尼，B·萊利。

Hello.

你好。

This is Kevin for Mayank from B. Riley.

我是 B. Riley 的 Mayank 的 Kevin。

Thanks for taking our question.

感謝您提出我們的問題。

I have a question about the future strategy in terms of you have those potent drugs plozasiran and zodasiran.

我有一個關於未來策略的問題，因為你們擁有強效藥物 plozasiran 和 zodasiran。

And can you elaborate on and how you would go on carve the target population, given that there are specific distinction in terms of mechanism or clinical defect by these two compounds?

鑑於這兩種化合物在機製或臨床缺陷方面存在具體區別，您能否詳細說明以及如何繼續開拓目標人群？

Thanks.

謝謝。

So Kevin, the way I tend to think of it, if you think of sort of lipids and lipoproteins as a bit of a continuum.

凱文，如果你把脂質和脂蛋白看成一個連續體的話，我傾向於這樣想。

And on one end, you have, familial hypercholesterolemia, a very LDL dominated disease, if you will, which then comes down into HEFH and patients that for other reasons, you just have very high cholesterols, but maybe normal triglycerides.

一方面，你患有家族性高膽固醇血症，這是一種以LDL 為主的疾病，如果你願意的話，它會歸結為HEFH 和患者，由於其他原因，你的膽固醇非常高，但甘油三酯可能正常。

And then you come into the middle where you have a mix, what used to be called mixed dyslipidemia now called mixed hyperlipidemia that untreated state, patients are maybe a combination of LDL and triglycerides, often with a lot of metabolic syndrome, obesity, diabetes, et cetera, about 20 million patients in the US and a lot of those patients are already on statins and already have some level of control of their LDL.

然後你就進入了中間，你有一個混合體，以前稱為混合性血脂異常，現在稱為混合性高脂血症，未經治療的狀態，患者可能是低密度脂蛋白和甘油三酯的組合，通常患有許多代謝綜合徵，肥胖，糖尿病，等等，美國大約有 2000 萬患者，其中許多患者已經在服用他汀類藥物，並且已經對 LDL 進行了一定程度的控制。

So from what's left untreated, it's largely in this triglyceride rich lipoproteins slash, remnant sort of a phenotype, if you will.

因此，從未處理的部分來看，它主要存在於富含三酸甘油酯的脂蛋白中，如果你願意的話，這是一種表型的殘餘物。

And then going further up that side, you get into the severe hypertriglyceridemia and yet at the outer end of that when you have SCS.

然後再往上走，你會出現嚴重的高三酸甘油酯血症，但在最外端，你會出現 SCS。

So if you think of it that way, I almost think of it like a U-shape with one into the EU is familial hypercholesterolemia and the other end of the USFCS and come down and in the middle, you have this 20 million patients with mixed hyperlipidemia.

所以如果你這樣想的話，我幾乎可以把它想像成一個 U 形，其中一個進入歐盟是家族性高膽固醇血症，另一端是 USFCS，然後往下走，在中間，有 2000 萬混合型患者高脂血症。

So you're on the one end, that's cholesterol.

所以你處於一方面，那就是膽固醇。

That's a very healthy place for Angptl3.

這對 Angptl3 來說是一個非常健康的地方。

And we've already seen that to an extent for instance, with Regeneron's multiple antibody works well on that side of the spectrum.

我們已經在某種程度上看到了這一點，例如再生元的多重抗體在這方面效果很好。

And then on the far side of the other spectrum with FCS and SHTG and the phenotypic FCS you have plozasiran So the real question is in the middle where you've got a mix of LDL and triglycerides in the phenotype of both drugs looked to be a very interesting drugs in that mixed dyslipidemia or mixed hyperlipidemia population.

然後在另一個譜的另一端，FCS 和 SHTG 以及表型 FCS，你有 plozasiran 所以真正的問題是在中間，兩種藥物的表型中都有 LDL 和甘油三酯的混合物，看起來是在混合性血脂異常或混合性高血脂症族群中非常有趣的藥物。

So what it means to us is that on the two ends of the spectrum, the drugs have target markets that make a lot of sense.

因此，這對我們來說意味著，在光譜的兩端，這些藥物都有非常有意義的目標市場。

And in the middle of both drugs look like they could be a major improvement over what's been available to practicing physicians for the last 30 years.

從這兩種藥物來看，它們可能是過去 30 年來執業醫生可用藥物的重大改進。

So that's kind of how we see it.

這就是我們的看法。

I hope, Kevin, that makes some sense to you.

凱文，我希望這對你有意義。

Brendan Smith, TD.

布倫丹·史密斯，TD。

Cohen.

科恩。

Thanks very much for taking the question.

非常感謝您提出問題。

Maybe just another quick one on pulmonary and then I have a broader follow-up.

也許只是另一個關於肺部的快速報道，然後我會有更廣泛的後續行動。

First, I actually just wanted to see if there's anything else specifically that you're seeing in the asthma patient data that's giving you more confidence to move into Phase 2?

首先，我實際上只是想看看您在氣喘患者數據中看到的其他具體內容是否讓您更有信心進入第二階段？

Maybe more of the point, if you've seen any of the high FeNO patient data yet, like if you're saying good FeNO knockdown or anything like that?

也許更重要的是，如果您看過任何高 FeNO 患者數據，例如您說良好的 FeNO 擊倒或類似的東西？

And then more broadly, I just wanted to check and see if there's any update on potential licensing or commercialization partnerships or maybe when we might get an update there and what that's looking like?

更廣泛地說，我只是想檢查潛在的許可或商業化合作夥伴關係是否有任何更新，或者我們什麼時候可以獲得更新以及情況如何？

Thanks very much.

非常感謝。

Sure.

當然。

Look, I think the biggest driver in moving and not waiting and moving towards that.

聽著，我認為最大的推動力是行動，而不是等待並朝著這個目標前進。

Phase 2 is the safety and tolerability that we've seen so far and the target engagement, and we're seeing good grade knockdown.

第二階段是我們迄今為止所看到的安全性和耐受性以及目標參與度，我們看到了良好的等級擊倒。

We've seen a lot of excitement from KOLs for the RAGE pathway and so it just makes sense just makes sense.

我們看到 KOL 對 RAGE 途徑感到非常興奮，所以這是有道理的。

So we're moving as quickly as we can there.

所以我們正在盡快行動。

On the on the partnering side, we are always virtually always in discussions as you can imagine, we have no control over timing.

在合作方面，正如你可以想像的那樣，我們幾乎總是在討論，我們無法控制時間。

And so I have nothing to report at this point, other than the fact that this is an important part of our business and we do expect to execute additional transactions.

因此，目前我沒有什麼可報告的，除了這是我們業務的重要組成部分並且我們確實希望執行更多交易。

Keay Nakae, Chardan.

凱·中江，查丹。

Thank you.

謝謝。

First question is there a rationale for the different sample sizes between SHASTA-3 and SHASTA-4 as one deliberately over sampled?

第一個問題是 SHASTA-3 和 SHASTA-4 之間故意過度採樣的不同樣本量有什麼理由嗎？

Not really.

並不真地。

So the design of the SHTG program was in many ways a result of our discussions with FDA about their overall expectations for what they wanted to see and efficacy database safety database, et cetera.

因此，SHTG 計劃的設計在許多方面都是我們與 FDA 討論他們對他們想要看到的內容和功效資料庫安全資料庫等的整體期望進行討論的結果。

And it just turned out that it could have been 350 in both.

結果發現兩者都可能是 350。

In the end, it practically it made sense to have 401, 300, but is really largely just driven by the practicalities to get the patient population that the agency was requested.

最後，實際上，擁有 401、300 是有意義的，但實際上很大程度上只是出於獲得該機構所要求的患者群體的實用性。

So it really is accidental, and you might say that they're different size.

所以這確實是偶然的，你可能會說它們的大小不同。

Okay.

好的。

And then in terms of the

然後就

-- .

——。

They're both way overpowered for efficacy, if you saw the results from SHASTA-2, they're both way overpowered for efficacy.

它們的功效都被壓倒了，如果你看到 SHASTA-2 的結果，它們的功效都被壓倒了。

Okay.

好的。

Well, that's great to hear.

嗯，很高興聽到這個消息。

Just in terms of the mix CVOT, since you have design, you're ready to submit for review, have you selected one of the two?

就混合CVOT而言，既然你已經設計好了，你已經準備好提交審查了，你選擇了兩者之一嗎？

And then based on the feedback, you still I guess have the option to switch?

然後根據反饋，我猜您仍然可以選擇切換？

Or how should we be thinking about where you're at with this?

或者我們該如何考慮你在這方面的處境？

So until we get into we have feedback and alignment with the regulators, it makes sense for us just to stand pat on that.

因此，在我們獲得回饋並與監管機構保持一致之前，我們堅持下去是有意義的。

We will give you, of course, all the information that we can once we once we have confirmation from the regulators that we are all aligned on what the study looks like.

當然，一旦我們得到監管機構的確認，我們在研究的內容上達成了一致，我們就會向您提供所有我們能提供的資訊。

So stay tuned on that, we're still working.

所以請繼續關注，我們仍在努力。

William Pickering, Bernstein.

威廉‧皮克林，伯恩斯坦。

Hi, good evening.

嗨，晚上好。

Congrats on the progress and thank you for taking my question.

恭喜您的進展，並感謝您提出我的問題。

On SHTG in SHASTA-2, you had a fairly sizable placebo effect of 17% at 24 weeks.

在 SHASTA-2 的 SHTG 中，第 24 週時安慰劑效應相當大，達到 17%。

Could you comment on whether you think that's a reasonable proxy for what to expect in the pivotal and if there are any strategies to potentially limit that?

您能否評論一下您是否認為這可以合理地預測關鍵時刻的情況，以及是否有任何策略可以潛在地限制這種情況？

But it's kind of interesting because if you actually look at the data, placebo was essentially plugging along at right around zero change.

但這很有趣，因為如果你真正查看數據，你會發現安慰劑基本上是在零變化左右。

And then at week 20, it was like zero.

然後到了第 20 週，這個數字幾乎是零。

And then at week 24, dips down to whatever minus 17, I guess and then that it was halfway back up to zero, four weeks later and then eight weeks later, it was right back to where it had been for the first 20 weeks.

然後在第 24 週，下降到負 17，我猜，然後一半回到零，四個星期後，然後八個星期後，它又回到了前 20 週的位置。

So it's just one of those were deals that.

所以這只是其中之一。

This is what makes it hard to do Placebo-controlled studies, your placebo just behaves, strangely, it at unpredictable times.

這就是安慰劑對照研究變得困難的原因，你的安慰劑只是在不可預測的時間表現得很奇怪。

And all of us just have to put up with that.

我們所有人都必須忍受這一點。

We did things in the trial to trying to minimize placebo.

我們在試驗中做了一些事情來盡量減少安慰劑的使用。

It changes in placebo.

它在安慰劑中發生變化。

But in the end, it's always difficult to really manage that.

但最終，真正做到這一點總是很困難。

And if I could just squeeze in a very quick follow-up.

如果我能快速跟進一下就好了。

What led you to pick the 25 milligram instead of the 50 milligram

是什麼讓您選擇 25 毫克而不是 50 毫克

?

？

And do you think that you'll be able to demonstrate a more compelling efficacy profile versus plozasiran at that dose?

您是否認為在該劑量下您將能夠展示出與 plozasiran 相比更引人注目的功效？

Well, 50 milligram and 25 milligram were very similar with respect to activity with respect to efficacy.

嗯，50 毫克和 25 毫克的活性和功效非常相似。

And that was not only in SHASTA-2, but that was also in MUIR.

這不僅存在於 SHASTA-2 中，也存在於 MUIR 中。

They just looked really close and yet there was a difference in tolerability.

他們只是看起來非常接近，但容忍度卻有差異。

And so it really was a benefit risk decision in the parlance of the regulatory parlance.

因此，用監管術語來說，這確實是利益風險決策。

But in our parlance as well.

但用我們的話來說也是如此。

You know, you look for, we put up with side effects in this business when we have to.

你知道，你會發現，當我們必須的時候，我們會忍受這個行業的副作用。

But if in fact, there's a dose available.

但事實上，有可用的劑量。

They essentially gives you full efficacy and has healed better safety and tolerability.

它們本質上為您提供了全部功效，並且具有更好的安全性和耐受性。

You take that one.

你拿那個。

Our overall assessment of the 25 milligram dose in both of those two large Phase 2 in which was it is that it's kind of indistinguishable from placebo.

我們對這兩個大型 2 期試驗中 25 毫克劑量的總體評估是，它與安慰劑沒有什麼區別。

The difference between active and placebo is so small.

活性藥物和安慰劑之間的差異非常小。

As to be it's not convincingly different at the 25 milligram dose groups in terms of safety and tolerability, right?

就安全性和耐受性而言，25 毫克劑量組並沒有令人信服的不同，對吧？

And that that mattered a lot, when the efficacy looked basically the same and 50 milligrams looked a little different from placebo.

這一點非常重要，因為 50 毫克的功效看起來與安慰劑基本相同，但看起來有些不同。

So we took advantage of the fact that we were at the top of the dose response curve for efficacy and we had a better safety and tolerability profile.

因此，我們利用了這樣一個事實：我們處於療效劑量反應曲線的頂部，並且我們具有更好的安全性和耐受性。

Patrick Trucchio, H.C. Wainwright & Co.

特魯基奧 (Patrick Trucchio)，H.C.溫賴特公司

Thanks.

謝謝。

Good evening.

晚安.

Just a couple of follow-up questions on the complement programs.

只是關於補充計劃的幾個後續問題。

Just first, I appreciate that dosing in the Phase 1/2a trial began last month, and I'm wondering though, if you can talk about potential timing of initial data in this trial evaluating AROCFB and kind of what you'd be looking for in that initial data later data give confidence in advancing this program?

首先，我很高興 1/2a 期試驗的給藥於上個月開始，但我想知道，您是否可以談談該試驗中評估 AROCFB 的初始數據的潛在時間以及您想要的內容在最初的數據中，後來的數據給了推進這個計劃的信心嗎？

And then secondly, if you can talk more broadly about the potential advantages of CFB relative to existing treatments for various complement mediated disease and how you envision CFB fitting in these different treatment paradigms?

其次，您是否可以更廣泛地談論 CFB 相對於現有的各種補體介導疾病治療方法的潛在優勢，以及您如何設想 CFB 適合這些不同的治療範式？

And then lastly, how should we think about this complement program relative to AROC3?

最後，我們該如何看待這個相對於 AROC3 的補充計畫？

And can you talk in more detail how these programs may progress in parallel?

您能否更詳細地談談這些項目如何並行進行？

Maybe I'll take the last first.

也許我會先選最後一個。

Thanks for the question.

謝謝你的提問。

So I think we will make a data-driven decision for C3 versus CFB.

因此，我認為我們將針對 C3 與 CFB 做出數據驅動的決策。

We think there are maybe some indications where C3 might work better, something like C3 glomerulopathy, where the disease is really driven by the accumulation of excessive C3 and then others where CFD might work better.

我們認為，在某些跡像中，C3 可能會發揮更好的作用，例如C3 腎小球病，這種疾病實際上是由過量C3 的積累引起的，而在其他跡像中，CFD 可能會發揮更好的作用。

But I think that will be really data driven.

但我認為這將是真正的數據驅動。

And then in terms of advantages, over some of the other therapeutics out there.

然後就優點而言，相對於其他一些治療方法。

I mean, I think the dosing advantage is really significant that we would have for both of these in terms of duration of effect AROC3, we're getting 88% knockdown that can be essentially maintained for three to four months after a single dose.

我的意思是，我認為就AROC3 的作用持續時間而言，我們對這兩種藥物的劑量優勢確實非常顯著，我們獲得了88% 的擊倒率，單次劑量後基本上可以維持三到四個月。

So I think if you're again looking at dosing quarterly versus other therapies that require either daily oral dosing or frequent subcutaneous dosing.

因此，我認為，如果您再次考慮每季給藥一次，與其他需要每日口服給藥或頻繁皮下給藥的療法相比。

I think there's a big advantage there.

我認為那裡有一個很大的優勢。

We'll see what the dosing regimen looks like for AROCFB.

我們將看看 AROCFB 的給藥方案是什麼樣的。

But based on the preclinical data, that's a very potent molecule.

但根據臨床前數據，這是一種非常有效的分子。

And so I'd expect something similar in terms of duration of effect.

因此，我預期效果持續時間也會類似。

And then data timing if the CFB study just got started, it's a healthy volunteer study.

然後數據計時，如果 CFB 研究剛開始，那麼它是一項健康的志願者研究。

And so the biomarker knockdown of circulating plasma CFP, that's the main efficacy or activity biomarker of interest.

因此，循環血漿 CFP 的生物標記敲低，是我們感興趣的主要功效或活性生物標記。

And we could potentially have something by year end for that.

我們可能會在年底前為此做出一些事情。

Thank you for your question.

謝謝你的問題。

This does conclude our question-and-answer session.

我們的問答環節到此結束。

I would now like to turn the call back over to Chris Anzalone for some closing remarks.

現在我想將電話轉回克里斯安札龍 (Chris Anzalone)，讓其發表一些結束語。

Thanking everyone for joining today, and we look forward to seeing you at the summer series starting later this month.

感謝大家今天的加入，我們期待在本月稍後開始的夏季系列賽中見到您。

This does conclude today's conference.

今天的會議到此結束。

You may now begin correct.

你現在可以開始正確的了。

Goodbye.

再見。