Arrowhead Pharmaceuticals Inc (ARWR) 2023 Q4 法說會逐字稿

Ladies and gentlemen welcome to the Arrowhead Pharmaceuticals conference call. (Operator Instructions) I will now hand the conference call over to Vince Anzalone, Vice President of Investor Relations for Arrowhead. Please go ahead, Vince.

女士們、先生們，歡迎參加 Arrowhead Pharmaceuticals 電話會議。 （操作員指示）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, Justin. Good afternoon and thank you for joining us today to discuss Arrowhead's results for its fiscal fourth quarter and year ended September 30, 2023.

謝謝你，賈斯汀。下午好，感謝您今天加入我們討論 Arrowhead 截至 2023 年 9 月 30 日的第四財季和年度業績。

With us today from management are President and CEO Dr. Chris Anzalone, who will provide an overview of the quarter; Dr. Javier San Martin, our Chief Medical Officer, who will provide an update on our mid and later stage clinical pipeline; Dr. James Hamilton, our Chief of Discovery & Translational Medicine, who will provide an update on our earlier stage programs; and Ken Myszkowski, our Chief Financial Officer, who will give a review of the financials. In addition, Tracie Oliver, our Chief Commercial Officer, and Patrick O'Brien, our Chief Operating Officer and General Counsel, will be available during the Q&A portion of the call.

今天與我們一起出席的是管理層的總裁兼首席執行官 Chris Anzalone 博士，他將概述本季的情況；我們的首席醫療官 Javier San Martin 博士將提供我們中後期臨床管道的最新資訊；我們的發現與轉化醫學主管 James Hamilton 博士，他將提供我們早期計畫的最新資訊；我們的財務長 Ken Myszkowski 將對財務狀況進行審查。此外，我們的商務長特雷西·奧利弗（Tracie Oliver）和首席營運長兼總法律顧問帕特里克·奧布萊恩（Patrick O'Brien）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

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 2019 年《證券交易法》第 21E 條含義內的某些前瞻性陳述。

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 10-K filed today and our quarterly reports on Form 10-Q.

1934. 除歷史事實陳述外的所有陳述均為前瞻性陳述，並受到許多風險和不確定性的影響，這些風險和不確定性可能導致實際結果與任何前瞻性陳述中表達的結果存在重大差異。有關這些風險和不確定性的更多詳細信息，請參閱我們向 SEC 提交的文件，包括今天提交的 10-K 表格和 10-Q 表格中的季度報告。

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 made significant progress toward reaching our 20 in 25 goal to grow our pipeline of RNAi therapeutics to a total of 20 clinical stage or marketed products by the year 2025. With yesterday's announcement of a CTA filing for ARO-DM1, our newest skeletal muscle targeted program being evaluated as a treatment for type 1 myotonic dystrophy, we now have 15 clinical stage programs; 10 are wholly-owned and 5 are being developed with partners.

謝謝，文斯。大家下午好，感謝您今天加入我們。 Arrowhead 在實現我們的25 種中的20 種目標方面取得了重大進展，即到2025 年將我們的RNAi 療法產品線擴大到總共20 種臨床階段或上市產品。昨天宣布ARO-DM1 的CTA 備案，我們最新的骨骼肌目標計畫正在被評估為 1 型強直性肌肉營養不良的治療方法，我們現在有 15 個臨床階段項目； 10 個是全資擁有的，5 個是與合作夥伴共同開發的。

We expect these 15 clinical programs to grow to 16 over the next month, with the addition of 1 more CTA this year. This will complete an extraordinarily productive year on the development front. In 2023, we will have nominated 9 new potential clinical candidates using our TRiM platform across 4 different tissues: liver, pulmonary, CNS, and skeletal muscle.

我們預計這 15 個臨床項目將在下個月增加到 16 個，今年還會增加 1 個 CTA。這將是發展方面卓有成效的一年。 2023 年，我們將使用我們的 TRiM 平台在 4 個不同組織中提名 9 名新的潛在臨床候選者：肝臟、肺部、中樞神經系統和骨骼肌。

In addition, we will have filed 4 CTAs for new clinical candidates during the calendar year. We believe this type of productivity is simply unmatched in our field. And it is particularly impressive given the size and market capitalization of our company. Even so, we expect more in 2024.

此外，我們將在本日曆年內為新的臨床候選人提交 4 份 CTA。我們相信這種生產力在我們的領域是無與倫比的。考慮到我們公司的規模和市值，這一成績尤其令人印象深刻。即便如此，我們預計 2024 年會有更多。

To understand these 15 clinical programs now, the 20 we will shortly have, the new targets we are planning to address, and the new cell types we will target over the years, is to understand the magnitude of patients we expect to treat and the value we can create over the long term.

要了解現在的這 15 個臨床項目、我們即將擁有的 20 個臨床項目、我們計劃解決的新目標以及我們多年來將針對的新細胞類型，就是要了解我們期望治療的患者數量和價值我們可以長期創造。

Of course there is too much there to discuss in this setting. So today we will focus on some of the accomplishments, events, and considerations that may drive and unlock value in the near term.

當然，在這種情況下有太多值得討論的地方。因此，今天我們將重點放在一些可能在短期內推動和釋放價值的成就、事件和考慮因素。

I see three primary areas: first, we are de-risking our pulmonary platform with knock-down and safety data in our clinical trials and toxicity data from our chronic tox studies. These enable us to move toward mid-stage studies addressing three main categories of chronic lung disease: inflammation, muco-obstruction, and interstitial lung disease; each of which has unmet treatment needs.

我看到三個主要領域：首先，我們正在透過臨床試驗中的擊倒和安全數據以及慢性毒物研究中的毒性數據來降低我們的肺部平台的風險。這些使我們能夠邁向中期研究，解決慢性肺病的三大類：發炎、黏膜阻塞和間質性肺病；每一個都有未滿足的治療需求。

Second, we are making good progress toward becoming a commercial company. We expect our initial commercial product to be plozasiran, formerly ARO-APOC3, in the treatment of familial chylomicronemia syndrome for which we will complete a Phase 3 study in Q2 2024, followed by our anticipated second indication for treating patients with severe hypertriglyceridemia or sHTG, and a later potential indication for treating the broad population of patients with mixed dyslipidemia and atherosclerotic cardiovascular disease. And lastly, we have directional guidance toward strengthening our balance sheet in a shareholder friendly way.

其次，我們在商業公司方面取得了良好進展。我們預計我們的初始商業產品是plozasiran（以前稱為ARO-APOC3），用於治療家族性乳糜微粒血症綜合徵，我們將在2024 年第二季度完成該綜合徵的3 期研究，隨後我們預計將有第二個適應症用於治療嚴重高三酸甘油脂血症或sHTG 患者，以及後來治療廣大患有混合性血脂異常和動脈粥狀硬化性心血管疾病的患者的潛在適應症。最後，我們提供了以股東友善的方式加強資產負債表的方向性指導。

Let's start with the pulmonary platform. We believe that Arrowhead is the first and only company to show clinically that RNAi can be harnessed to silence gene expression in the human lung. This is important and marks the accomplishment of a key long-term goal we set for ourselves several years ago. We have always thought that once we have human safety and activity proof of concept with one candidate, it will unlock value in the entire platform and provide confidence that other programs could work similarly, much like our current expectations for new liver programs.

讓我們從肺平台開始。我們相信 Arrowhead 是第一家也是唯一一家在臨床上證明 RNAi 可用於沉默人類肺部基因表現的公司。這很重要，標誌著我們幾年前為自己設定的關鍵長期目標的實現。我們一直認為，一旦我們對某一候選者進行了人類安全和活動概念驗證，它將釋放整個平台的價值，並為其他項目可以類似地發揮作用提供信心，就像我們目前對新肝臟項目的期望一樣。

So, let's talk about important de-risking steps. First, we think we have confirmation that we have adequately addressed the chronic GLP toxicology issues of our first-generation ARO ENaC candidates. In that program, we saw findings of local lung inflammation in chronic rat and monkey toxicology studies. We determined that this result was consistent with macrophage overload syndrome. And thus we needed to make next generation candidates with improved potency and enhanced duration of effect. So we could stretch out the dosing interval and reduce exposure. I think we are now over that initial hurdle.

那麼，我們來談談重要的降低風險的步驟。首先，我們認為我們已經確認我們已經充分解決了第一代 ARO ENaC 候選藥物的慢性 GLP 毒理學問題。在這個計畫中，我們在慢性大鼠和猴子毒理學研究中看到了局部肺部發炎的發現。我們確定此結果與巨噬細胞過載症候群一致。因此，我們需要生產具有更高效力和更長效果持續時間的下一代候選藥物。因此我們可以延長給藥間隔並減少暴露。我認為我們現在已經克服了最初的障礙。

We've received chronic toxicology results in both rodent and primate species for ARO-RAGE and ARO-MMP7. James will talk about the specifics. But the takeaway is that the NOAELs or No Observed Adverse Effect Levels suggest sufficient safety margins to move confidently into Phase 2 studies. These were welcomed results and I believe, represent substantial de-risking for the entire pulmonary platform.

我們已收到 ARO-RAGE 和 ARO-MMP7 在囓齒動物和靈長類動物中的慢性毒理學結果。詹姆斯將談論具體細節。但重點是，NOAEL 或未觀察到的不良效應水平表明有足夠的安全裕度，可以自信地進入第二階段研究。這些結果受到歡迎，我相信，這代表了整個肺部平台的顯著降低風險。

Once we select a dose and dose interval for each candidate, we plan to interact with regulatory authorities in 2024 to discuss all results to date, including toxicology, and our plans for further clinical development.

一旦我們為每個候選藥物選擇了劑量和劑量間隔，我們計劃在 2024 年與監管機構進行互動，討論迄今為止的所有結果，包括毒理學，以及我們進一步臨床開發的計劃。

Next, we want to ensure that clinical safety and tolerability are acceptable. We now have 3 pulmonary programs in first-in-human studies and safety results have been consistent with no concerning safety signals across all 3 programs in 145 patients or healthy volunteers on active drug.

接下來，我們希望確保臨床安全性和耐受性是可以接受的。我們現在有 3 個肺部項目正在進行首次人體研究，安全性結果與所有 3 個項目在 145 名服用活性藥物的患者或健康志願者中沒有出現任何令人擔憂的安全信號一致。

Third, we need to ensure that our pulmonary drug candidates are doing what they are intended to do. We still need patient data in ARO-MMP7 and ARO-MUC5AC to understand this. But ARO-RAGE data have been very encouraging.

第三，我們需要確保我們的肺部候選藥物正在發揮其應有的作用。我們仍然需要 ARO-MMP7 和 ARO-MUC5AC 中的患者數據來理解這一點。但 ARO-RAGE 的數據非常令人鼓舞。

Normal healthy volunteers showed 89% mean max knockdown and 95% max knockdown of circulating sRAGE after 2 doses of 184 milligrams ARO-RAGE. At 92 milligrams, healthy volunteers showed a mean max knockdown of 80% and max knockdown of 90% after 2 doses.

正常健康志願者服用 2 劑 184 毫克 ARO-RAGE 後，循環 sRAGE 的平均最大抑制率為 89%，最大抑制率為 95%。在 92 毫克劑量下，健康志願者在 2 次劑量後表現出平均最大擊倒率為 80%，最大擊倒率為 90%。

We are still collecting data from asthma patients. But so far they are mapping on top of those from normal healthy volunteers, as we expected. Together, I believe these data are important for the ARO-RAGE program and, more broadly, serve to de-risk the entire pulmonary franchise.

我們仍在收集哮喘患者的數據。但到目前為止，正如我們所預期的那樣，他們繪製的地圖是在正常健康志願者的地圖上繪製的。總之，我相信這些數據對於 ARO-RAGE 計劃非常重要，更廣泛地說，有助於降低整個肺部疾病的風險。

These data give us confidence that one; we have chronic tox coverage to move confidently into Phase 2 studies for ARO-RAGE and ARO-MMP7. Two, The drug candidates have been generally well tolerated in humans; and three, We are seeing deep and durable knockdown in the ARO-RAGE clinical program that tracks with what we saw in animal studies.

這些數據讓我們有信心；我們擁有慢性毒物覆蓋範圍，可以自信地進入 ARO-RAGE 和 ARO-MMP7 的 2 期研究。第二，候選藥物在人類普遍具有良好的耐受性；第三，我們在 ARO-RAGE 臨床計畫中看到了深度和持久的抑制，該計畫與我們在動物研究中看到的結果一致。

The next step is to interrogate whether RAGE knockdown leads to a favorable clinical effect in patients. Upstream of hard clinical outcomes or FEV1, there are biomarkers that can inform on whether ARO-RAGE is engaging inflammatory pathways. We are approaching a time during the coming months, where we may have data on ARO-RAGE in asthma patients to make that assessment.

下一步是詢問 RAGE 敲除是否會為患者帶來良好的臨床效果。在硬臨床結果或 FEV1 的上游，有一些生物標記可以告知 ARO-RAGE 是否參與發炎途徑。我們即將在未來幾個月內獲得氣喘患者 ARO-RAGE 的數據來進行評估。

We are currently dosing mild-to-moderate asthma patients and enrolling patients with high baseline FeNO to potentially enrich for an anti-inflammatory signal. I believe that signal would represent a significant further de-risking event. So we are working quickly to get high FeNO patients enrolled.

我們目前正在對輕度至中度氣喘患者進行給藥，並招募具有高基線 FeNO 的患者，以潛在地豐富抗發炎訊號。我相信這訊號將代表進一步的重大去風險事件。因此，我們正在迅速努力讓高 FeNO 患者入組。

The next area where I think we are creating substantial value is our progress toward becoming a commercial company. Our Phase 3 study of plozasiran in patients with familial chylomicronemia syndrome is approaching completion. And we expect the last patient visit to be in the second quarter of 2024. That is a big step for a development stage biotech company. We are carefully considering launch strategies for plozasiran and look forward to speaking more about those soon.

我認為我們正在創造巨大價值的下一個領域是我們在成為商業公司方面取得的進展。我們對 plozasiran 在家族性乳糜微粒血症症候群患者中的 3 期研究即將完成。我們預計最後一次患者就診將在 2024 年第二季。對於處於發展階段的生技公司來說，這是邁出的一大步。我們正在仔細考慮 plozasiran 的發布策略，並期待很快就這些策略進行更多討論。

So where do we go after FCS? Data from Phase 2 studies of both plozasiran and zodasiran, formerly ARO-ANG3, have been very compelling. And our presentations and webcast around the

那麼FCS之後我們該去哪裡呢？ plozasiran 和 zodasiran（以前稱為 ARO-ANG3）的 2 期研究數據非常引人注目。我們的演示和網路廣播圍繞

American Heart Meeting earlier this month was well received by physicians, industry, and the investment community.

本月稍早舉行的美國心臟會議受到了醫生、產業和投資界的好評。

For plozasiran, we see a clear opportunity to treat patients with severe hypertriglyceridemia, or sHTG. We believe there are 3 to 4 million people in the U.S. with triglycerides over 500 mg/dl, with approximately 1 million of them with TGs greater than 880. There are very limited treatment options for these patients.

對於 plozasiran，我們看到了治療嚴重高三酸甘油脂血症（sHTG）患者的明顯機會。我們認為，美國有 300 至 400 萬人的三酸甘油酯超過 500 mg/dl，其中約 100 萬人的 TG 高於 880。這些患者的治療選擇非常有限。

Further, we anticipate an sHTG approval based upon studies demonstrating a lowering of triglycerides during 1 year of treatment, with an adequate safety profile. In Phase 2 studies, plozasiran reduced TGs to lower than 500 in virtually all patients, and many had TGs fall to normal levels.

此外，我們預計 sHTG 會獲得批准，因為研究表明治療 1 年期間三酸甘油酯會降低，並且具有足夠的安全性。在第 2 期研究中，plozasiran 將幾乎所有患者的 TG 降低至 500 以下，許多患者的 TG 降至正常水平。

We are presented with a compelling set of facts: a large pool of patients without adequate treatment options a clear and relatively short regulatory pathway, and a drug candidate that has been consistent and very effective in Phase 1 and Phase 2 studies with good tolerability.

我們看到了一組令人信服的事實：大量患者沒有足夠的治療選擇，明確且相對較短的監管途徑，以及在1 期和2 期研究中表現一致且非常有效且具有良好耐受性的候選藥物。

We have had productive interactions with FDA, including an end of Phase 2 meeting, to discuss the design of a Phase 3 clinical program in sHTG patients. We are finalizing planning. And I expect we will launch the studies early in 2024.

我們與 FDA 進行了富有成效的互動，包括在 2 期會議結束時討論 sHTG 患者 3 期臨床計劃的設計。我們正在敲定計劃。我預計我們將在 2024 年初啟動這些研究。

Beyond FCS and sHTG, we continue to see attractive opportunities to help a broader population of patients with plozasiran or with zodasiran. Both candidates have shown to substantially reduce remnant cholesterol, an increasingly appreciated risk factor of cardiovascular disease.

除了 FCS 和 sHTG 之外，我們繼續看到誘人的機會來幫助更廣泛的 plozasiran 或 zodasiran 患者。兩種候選藥物都顯示出可以顯著降低殘餘膽固醇，這是一種日益受到重視的心血管疾病的危險因子。

I expect that we will conduct a cardiovascular outcome trial, or CVOT, and that we will launch it in the middle of 2024. We have been planning to run a CVOT with plozasiran. But given the exciting data we presented at AHA in mixed dyslipidemia patients, we are now considering whether plozasiran or zodasiran would be the better candidate.

我預計我們將進行心血管結果試驗（CVOT），並將在 2024 年中期啟動。我們一直計劃使用 plozasiran 進行 CVOT。但鑑於我們在 AHA 上公佈的混合性血脂異常患者的令人興奮的數據，我們現在正在考慮 plozasiran 或 zodasiran 是否是更好的候選人。

We expect to decide which is better suited for this patient population over the coming months. This is a good problem to have, as both appear to be potentially powerful agents in this large market. And we simply want to try to ensure we are moving the best candidate forward in this space.

我們預計在未來幾個月內決定哪種藥物更適合該患者群體。這是一個很好的問題，因為兩者似乎都是這個大市場中潛在的強大代理人。我們只是想努力確保我們在這個領域推動最好的候選人前進。

Also on the late-stage side of our business, Takeda is enrolling patients in the Phase 3 study of fazirsiran. It is my understanding that they intend to open approximately 90 sites world-wide to help ensure the program moves quickly to an approvable endpoint that could be met after 2 years of treatment.

同樣在我們業務的後期階段，武田正在招募患者參加 fazirsiran 的 3 期研究。據我了解，他們打算在全球開設約 90 個站點，以幫助確保該計劃快速達到可在治療 2 年後實現的可批准終點。

Our wholly-owned programs, discovery engine, and bourgeoning commercial presence are all exciting components of our business that, we believe, will create substantial value going forward. They will also require significant capital over the coming years. And we are focused on building out our balance sheet to ensure that we can make these important investments.

我們的全資項目、發現引擎和蓬勃發展的商業存在都是我們業務中令人興奮的組成部分，我們相信，它們將在未來創造巨大的價值。未來幾年他們還需要大量資金。我們專注於建立我們的資產負債表，以確保我們能夠進行這些重要的投資。

To that end, we are actively working on opportunities to bring in capital in shareholder friendly ways. And we believe there are several good options in front of us.

為此，我們正在積極尋找機會，以股東友善的方式引入資本。我們相信我們面前有幾個不錯的選擇。

For instance, we are exploring specific product financing for the plozasiran sHTG Phase 3 study and separately a possible CVOT, whether done with plozasiran or zodasiran. We believe we could source sufficient capital for those studies in return for limited royalties on those products.

例如，我們正在探索 plozasiran sHTG 3 期研究的特定產品融資，以及單獨可能的 CVOT，無論是使用 plozasiran 還是 zodasiran 進行。我們相信，我們可以為這些研究籌集足夠的資金，以換取這些產品的有限特許權使用費。

In addition, we have discussed business development in the past. We now have 5 different platforms that incorporate the design of high-quality RNAi molecules that target 5 different cell types: hepatocytes, skeletal muscle, pulmonary, adipose, and CNS. We believe this broad ability to deliver highly potent RNAi molecules to -- a variety of tissues is both scarce and valuable, and could enable dozens of new drugs.

此外，我們過去也討論過業務發展。我們現在擁有 5 個不同的平台，其中結合了針對 5 種不同細胞類型的高品質 RNAi 分子的設計：肝臟細胞、骨骼肌、肺細胞、脂肪和中樞神經系統。我們相信，這種將高效 RNAi 分子遞送至多種組織的廣泛能力既稀缺又有價值，並且可以使數十種新藥成為可能。

We believe there is ample room to work with partners and also continue to build an extensive wholly-owned pipeline. This is intended to continue to let our discovery engine move quickly while ensuring that one, we focus on a more limited set of wholly-owned assets that provide our commercial team with a level of synergy and efficiency. Two, we continue to have access to necessary capital outside the capital markets. Three, we can continue to build more passive value as our partners invest in development and commercialization. And four, we can continue to serve patients.

我們相信有足夠的空間與合作夥伴合作，並繼續建立廣泛的全資管道。這樣做的目的是繼續讓我們的發現引擎快速發展，同時確保我們專注於一組更有限的全資資產，為我們的商業團隊提供一定程度的協同作用和效率。第二，我們繼續能夠在資本市場之外獲得必要的資本。第三，隨著我們的合作夥伴投資開發和商業化，我們可以繼續創造更多被動價值。第四，我們可以繼續為病人服務。

As we are able to provide better clarity relating to the sources and magnitude of new capital, I believe a clear overhang in our stock may be removed. There is a lot of high-quality work going on at Arrowhead, and substantial potential value to be unlocked as we solidify our balance sheet. Stay tuned for details when we're able to talk more about it.

由於我們能夠更清楚地了解新資本的來源和規模，我相信我們庫存中的明顯積壓可能會被消除。 Arrowhead 正在進行大量高品質的工作，隨著我們鞏固資產負債表，巨大的潛在價值將被釋放。當我們能夠進一步討論時，請繼續關注詳細資訊。

I want to highlight one last event from the quarter that is important. We announced that GSK reached an agreement with Janssen to transfer exclusive worldwide rights to further develop and commercialize JNJ-3989 to GSK. If you recall,

我想強調本季最後一件重要的事件。我們宣布葛蘭素史克與楊森達成協議，將進一步開發和商業化 JNJ-3989 的全球獨家權利轉讓給葛蘭素史克。如果你還記得的話，

Janssen announced that they were discontinuing hepatitis B research and later announced that they were winding down most of their infectious disease and vaccine programs. JNJ-3989 was one of the discontinued programs of this strategic decision. That created uncertainty about its future. Janssen was a good partner. And we are confident that GSK will continue the diligent work Janssen started.

楊森宣布他們將停止乙型肝炎研究，後來宣布他們將逐步結束大部分傳染病和疫苗計畫。 JNJ-3989是此策略決策中停產的項目之一。這給它的未來帶來了不確定性。詹森是個很好的合作夥伴。我們相信葛蘭素史克將繼續楊森開始的辛勤工作。

This transaction also builds on Arrowhead's relationship with GSK, which includes the 2021 exclusive license of GSK4532990, formerly ARO-HSD, an investigational RNAi therapeutic currently in a Phase 2 study as a potential treatment for patients with alcohol-related and non-alcohol related liver diseases. We look forward to continuing our productive relationship with GSK.

這項交易也建立在Arrowhead 與GSK 的關係基礎上，其中包括GSK4532990（以前稱為ARO-HSD）的2021 年獨家許可，這是一種研究性RNAi 治療藥物，目前正在進行2 期研究，作為酒精相關和非酒精相關肝臟患者的潛在治療方法疾病。我們期待繼續與葛蘭素史克保持富有成效的關係。

With that overview, I'd now like to turn the call over to Dr. Javier San Martin. Javier?

有了上述概述，我現在想將電話轉給哈維爾·聖馬丁博士。哈維爾？

Thank you, Chris, and good Afternoon everyone. I want to focus on the significant progress we've made on plozasiran, formerly ARO-APOC3, and zodasiran, formerly ARO-ANG3. This includes presentations at the American Heart Association meeting with Phase 2 data on the MUIR and SHASTA-2 studies of plozasiran and the ARCHES-2 study of zodasiran, a KOL webinar on the significance of these data, and recent interactions we've had with the FDA on our plans for Phase 3 studies.

謝謝克里斯，大家下午好。我想重點介紹我們在 plozasiran（以前稱為 ARO-APOC3）和 zodasiran（以前稱為 ARO-ANG3）上取得的重大進展。這包括在美國心臟協會會議上介紹 plozasiran 的 MUIR 和 SHASTA-2 研究以及 zodasiran 的 ARCHES-2 研究的 2 期數據、關於這些數據重要性的 KOL 網路研討會，以及我們最近與FDA 批准我們的3 期研究計劃。

Let's start with a review of what plozasiran is and then discuss the data presented at AHA. Plozasiran is designed to reduce production of Apolipoprotein C-III, or APOC3, a component of triglyceride rich lipoproteins, or TRLs, and a key regulator of triglyceride metabolism. APOC3 increases plasma TG levels by inhibiting breakdown of TRLs by lipoprotein lipase and uptake of TRL remnants by hepatic receptors in the liver.

讓我們先回顧一下 plozasiran 是什麼，然後再討論 AHA 上提供的數據。 Plozasiran 旨在減少載脂蛋白 C-III（APOC3）的產生，載脂蛋白 C-III 是富含三酸甘油酯的脂蛋白（TRL）的成分，也是三酸甘油酯代謝的關鍵調節劑。 APOC3 透過抑制脂蛋白脂肪酶對 TRL 的分解以及肝臟中肝受體對 TRL 殘餘物的攝取來增加血漿 TG 水平。

Plozasiran is being developed as a treatment for patients with familial chylomicronemia syndrome, severe hypertriglyceridemia, and mixed dyslipidemia. These are 3 distinct patient populations with very different phenotypes.

Plozasiran 正在開發用於治療家族性乳糜微粒血症綜合症、嚴重高三酸甘油酯血症和混合性血脂異常患者。這是 3 個不同的患者群體，具有截然不同的表型。

Familial chylomicronemia syndrome, or FCS, is a severe and ultrarare genetic disease characterized by extremely high TG levels, typically over 1000 mg/dl, leading to high risk of acute pancreatitis that usually requires hospitalization and can be fatal.

家族性乳糜微粒血症症候群(FCS) 是一種嚴重且極為罕見的遺傳性疾病，其特徵是TG 水平極高，通常超過1000 mg/dl，導致急性胰臟炎的高風險，通常需要住院治療並可能致命。

We are currently conducting the PALISADE Phase 3 study in 75 patients with FCS. The primary endpoint of the study is percent change from baseline in fasting TG. PALISADE is on schedule to complete in Q2 of 2024.

我們目前正在對 75 名 FCS 患者進行 PALISADE 3 期研究。研究的主要終點是空腹三酸甘油酯相對於基線的變化百分比。 PALISADE 計劃於 2024 年第二季完成。

Severe hypertriglyceridemia, or SHTG, is characterized by marked elevations in TG levels, typically over 500 mg/dl, which can also lead to increased risk of acute pancreatitis, as well as an increased risk of cardiovascular disease.

嚴重高三酸甘油酯血症（SHTG）的特徵是 TG 水平顯著升高，通常超過 500 mg/dl，這也會導致急性胰臟炎的風險增加，以及心血管疾病的風險增加。

We conducted the Phase 2 SHASTA-2 study and reported data at AHA. We are also working on initiating Phase 3 studies, SHASTA-3 and SHASTA-4 in early 2024. I will discuss the AHA data and Phase 3 study design in a moment.

我們進行了 SHASTA-2 2 期研究並在 AHA 報告了數據。我們也致力於在 2024 年初啟動第 3 階段研究、SHASTA-3 和 SHASTA-4。我稍後將討論 AHA 數據和第 3 階段研究設計。

Lastly, mixed dyslipidemia is the presence of high TGs, and remnant cholesterol, often with low HDL cholesterol. Remnant cholesterol is believed to be a major contributor to the residual risk of atherosclerotic cardiovascular disease after LDL is well controlled.

最後，混合性血脂異常是指存在高三酸甘油酯和殘餘膽固醇，通常伴隨低高密度脂蛋白膽固醇。殘餘膽固醇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 conducted the Phase 2 MUIR study in patients with mixed dyslipidemia and reported those data at AHA. We are currently working on key features of the study design including patient population selection for a potential Phase 3 study in patients with ASCVD and mixed dyslipidemia.

我們對混合性血脂異常患者進行了 2 期 MUIR 研究，並在 AHA 報告了這些數據。我們目前正在研究研究設計的關鍵特徵，包括針對 ASCVD 和混合性血脂異常患者進行潛在 3 期研究的患者群體選擇。

We presented data at AHA for these last two patient populations: SHTG and mixed dyslipidemia. In the Phase 2 SHASTA-2 study of plozasiran in 226 subjects with sHTG who had baseline TGs greater than 500 mg/dl, 2 doses of 10, 25, or 50 mg of plozasiran once every 12 weeks reduced TGs to near normal levels and more than 90% of patients achieved TG levels below 500 mg/dl, which is the risk threshold for acute pancreatitis.

我們在 AHA 上展示了最後兩個患者群體的數據：SHTG 和混合性血脂異常。在plozasiran 的2 期SHASTA-2 研究中，226 名基線TG 大於500 mg/dl 的sHTG 受試者接受了2 劑10、25 或50 mg 的plozasiran，每12 週一次，將TG 降低至接近正常水平或更多超過 90% 的患者 TG 水平低於 500 mg/dl，這是急性胰臟炎的風險閾值。

Plozasiran achieved mean maximum reductions of up to 90% in APOC3 and 87% in TGs. At 24 weeks, 12 weeks after the second dose, serum APOC3 remained 79% below baseline. And TGs were 74% below baseline, with reduction in remnant cholesterol of 63%, while HDL-cholesterol increased 68% above baseline.

Plozasiran 的 APOC3 平均最大降低幅度高達 90%，TG 平均最大降低幅度高達 87%。第 24 週，即第二次給藥後 12 週，血清 APOC3 仍低於基線 79%。 TG 比基線低 74%，殘餘膽固醇減少 63%，而 HDL 膽固醇比基線增加 68%。

In the Phase 2 MUIR study of plozasiran in 353 subjects with mixed dyslipidemia who had fasting TGs between 150 and 499 mg/dl and either LDL-cholesterol greater than 70 mg/dl or non-HDL-cholesterol greater 100 mg/dl. Subjects in the study received 2 doses of 10, 25, or 50 mg of plozasiran at baseline and at week 12 or 2 doses of 50 mg at baseline and week 24.

在plozasiran 的2 期MUIR 研究中，對353 名患有混合性血脂異常的受試者進行了研究，這些受試者的空腹TG 介於150 至499 mg/dl 之間，並且LDL 膽固醇大於70 mg /dl 或非HDL 膽固醇大於100 mg/dl。研究中的受試者在基線和第 12 週接受 2 劑 10、25 或 50 mg 的 plozasiran，或在基線和第 24 週接受 2 劑 50 mg。

Plozasiran-treated subjects demonstrated a mean maximum reduction in APOC3 of up to 89% and robust reductions in atherogenic lipoproteins. At 24 weeks, plozasiran reduced TGs by 64%, remnant cholesterol by 54%, ApoB by 19%, and Non-HDL-cholesterol by 27%, while increasing HDL-cholesterol by 51%.

Plozasiran 治療的受試者表現出 APOC3 平均最大減少高達 89%，並且致動脈粥樣硬化脂蛋白顯著減少。 24 週時，plozasiran 使 TG 降低 64%，殘餘膽固醇降低 54%，ApoB 降低 19%，非 HDL 膽固醇降低 27%，同時 HDL 膽固醇增加 51%。

These were very encouraging results. And they received a lot of attention at AHA.

這些都是非常令人鼓舞的成果。他們在 AHA 上受到了很多關注。

After the presentations, we hosted a webcast featuring three experts in the treatment and management of lipid and lipoprotein disorders: Daniel Gaudet, Professor of Medicine at Universite de Montreal, who discussed plozasiran in the context of the current treatment landscape for severe hypertriglyceridemia.

演講結束後，我們主持了一場由脂質和脂蛋白疾病治療和管理領域的三位專家主持的網路廣播：蒙特利爾大學醫學教授Daniel Gaudet，他在當前嚴重高三酸甘油酯血症治療前景的背景下討論了plozasiran。

Borge Nordestgaard, Professor and Chief Physician, Copenhagen University Hospital, University of Copenhagen, Denmark, who discussed the emergent role of remnant cholesterol in cardiovascular disease. And, Steven Nissen, Chief Academic Officer for the Heart and Vascular Institute at the Cleveland Clinic, who discussed why the decrease in atherogenic lipoproteins observed with Plozasiran, has the potential to prevent CV outcomes. A replay of that webcast is available on our website if you missed it.

丹麥哥本哈根大學哥本哈根大學醫院教授兼主任醫師 Borge Nordestgaard 討論了殘餘膽固醇在心血管疾病中的新作用。克利夫蘭診所心臟和血管研究所首席學術官史蒂文·尼森 (Steven Nissen) 討論了為什麼用 Plozasiran 觀察到的致動脈粥樣硬化脂蛋白減少有可能預防心血管結局。如果您錯過了該網路廣播，可以在我們的網站上重播。

My takeaway was that all 3 experts agreed that plozasiran has a unique profile and great potential in FCS, sHTG, and in patients with ASCVD and mixed dyslipidemia. The support of these notable experts gives us additional confidence as we embark on Phase 3 studies to further evaluate plozasiran.

我的結論是，所有 3 位專家都同意 plozasiran 在 FCS、sHTG 以及 ASCVD 和混合性血脂異常患者中具有獨特的特徵和巨大潛力。當我們著手進一步評估 plozasiran 的第三階段研究時，這些著名專家的支持給了我們額外的信心。

So, what will the sHTG Phase 3 studies look like? We had an end of Phase 2 meeting with the FDA. And our plan is to do 2 similar studies: SHASTA-3 and SHASTA-4 that together will be composed of approximately 700 patients, all with TGs greater than 500 mg/dl. The primary endpoint is lowering TGs after 1 year. We will include a subset of patients at higher risk of acute pancreatitis. We will provide more detail on that as we get the studies initiated in early 2024.

那麼，sHTG 第三階段研究會是什麼樣子呢？我們與 FDA 舉行了第二階段會議的結束。我們的計劃是進行 2 項類似的研究：SHASTA-3 和 SHASTA-4，總共將由大約 700 名患者組成，所有患者的 TG 均大於 500 mg/dl。主要終點是 1 年後降低 TG。我們將納入一部分急性胰臟炎風險較高的患者。當我們在 2024 年初啟動研究時，我們將提供更多詳細資訊。

We will also have a third study that enrolled patients with moderately elevated TGs to add to our safety database. We expect these studies to all be completed around the same time.

我們也將進行第三項研究，招募 TG 中度升高的患者，以加入我們的安全資料庫。我們預計這些研究將在大約同一時間完成。

All in all, our interactions with FDA have been productive and helpful. We believe that we have incorporated their feedback and look forward to continued dialogue with the agency as we get closer to an NDA filing following completion of the

總而言之，我們與 FDA 的互動是富有成效且有益的。我們相信，我們已經採納了他們的回饋，並期待在完成 NDA 後，與該機構繼續對話。

PALISADE study in patients with FCS and as we move forward with additional Phase 3 studies in sHTG and mixed dyslipidemia.

PALISADE 研究針對 FCS 患者，並且我們正在推進 sHTG 和混合性血脂異常的其他 3 期研究。

We also presented data at AHA on zodasiran, which received a lot of attention. Zodasiran is designed to reduce production of angiopoietin-like protein 3, or ANGPTL3, which is a hepatocyte expressed regulator of lipid and lipoprotein metabolism with multiple potential modes of action, including inhibition of lipoprotein lipase and endothelial lipase.

我們也在 AHA 上展示了 zodasiran 的數據，引起了很多關注。 Zodasiran 旨在減少血管生成素樣蛋白3 或ANGPTL3 的產生，ANGPTL3 是一種肝細胞表達的脂質和脂蛋白代謝調節劑，具有多種潛在的作用模式，包括抑制脂蛋白脂肪酶和內皮脂肪酶。

In the Phase 2 ARCHES-2 study of zodasiran in 204 subjects with mixed dyslipidemia who had baseline TGs between 150 and 499 mg/dl and either LDL-cholesterol greater than 70 mg/dl or non-HDL-cholesterol greater 100 mg/dl, 2 doses of 50 mg, 100 mg, or 200 mg of zodasiran once every 12 weeks reduced the expression of ANGPTL3 and decreased atherogenic lipoproteins.

在zodasiran 的2 期ARCHES-2 研究中，204 名患有混合性血脂異常的受試者的基線TG 介於150 至499 mg/dl 之間，且LDL 膽固醇大於70 mg/dl 或非HDL 膽固醇大於100 mg/dl，每 12 週一次 2 劑 50 mg、100 mg 或 200 mg zodasiran 可減少 ANGPTL3 的表達並減少致動脈粥樣硬化脂蛋白。

Treatment with zodasiran resulted in substantial reductions of ANGPTL3 up to 74%, TGs up to 63%, LDL-cholesterol up to 20%, remnant cholesterol up to 82%, and ApoB up to 22% all at week 24.

在第 24 週，zodasiran 治療導致 ANGPTL3 大幅降低高達 74%，TG 降低高達 63%，LDL 膽固醇降低高達 20%，殘餘膽固醇降低高達 82%，ApoB 降低高達 22%。

Zodasiran was also associated with a relative reduction in liver fat fraction at week 24, with no adverse events related to liver function test changes reported to date.

Zodasiran 也與第 24 週時肝臟脂肪分數的相對降低有關，迄今尚未報告與肝功能測試變化相關的不良事件。

Plozasiran and zodasiran continued to show favorable safety profiles. Treatment emergent adverse events reported to date reflect the comorbidities and underlying conditions of the study populations.

Plozasiran 和 zodasiran 繼續表現出良好的安全性。迄今為止報告的治療中出現的不良事件反映了研究人群的合併症和潛在狀況。

As I mentioned before, we are currently considering multiple Phase 3 study designs and making decisions on patient population selection for mixed dyslipidemia in patients with atherosclerotic cardiovascular disease. We will talk more about that in 2024 after we have further interactions with FDA about our proposed plan.

正如我之前提到的，我們目前正在考慮多個 3 期研究設計，並就動脈粥狀硬化性心血管疾病患者混合性血脂異常的患者群體選擇做出決定。在我們與 FDA 就我們擬議的計劃進行進一步互動後，我們將在 2024 年更多地討論這一問題。

I will now turn the call over to Dr. James Hamilton. James?

我現在將把電話轉給詹姆斯·漢密爾頓博士。詹姆士？

Thank you, Javier. I believe the productivity of our discovery organization is unrivalled. This is partly due to the efficiency and scalability of siRNA therapeutics and specifically of our proprietary TRiM platform, but more importantly a product of the culture of speed and innovation at Arrowhead.

謝謝你，哈維爾。我相信我們的發現組織的生產力是無與倫比的。這部分歸功於 siRNA 療法的效率和可擴展性，特別是我們專有的 TRiM 平台，但更重要的是 Arrowhead 速度和創新文化的產物。

We continue to find ways to outperform others in the RNA therapeutics space with a highly productive and lean organization.

我們不斷尋找方法，透過高效且精益的組織，在 RNA 治療領域超越其他公司。

In 2023 alone, we completed discovery and optimization work across 5 different delivery platforms and nominated 9 clinical candidates. Each then may go on to the IND-enabling phase, including GLP toxicology studies, clinical supply manufacturing, as well as preparation and submission of regulatory filings.

光是 2023 年，我們就完成了 5 個不同交付平台的發現和優化工作，並提名了 9 位臨床候選人。然後每個項目都可以進入 IND 授權階段，包括 GLP 毒理學研究、臨床供應製造以及監管文件的準備和提交。

We are also working on a discovery pipeline of similar size for 2024. This high level of productivity is how we intend to reach our 20 in 25 development goal. Our discovery stage pipeline is, for the most part, kept confidential until we are approaching a CTA, or at times until we file a CTA. So you will likely start hearing more about the newly nominated clinical candidates over the coming quarters.

我們也致力於 2024 年類似規模的發現管道。這種高水準的生產力是我們打算實現 25 中 20 的開發目標的方式。我們的發現階段管道在很大程度上是保密的，直到我們接近 CTA，或有時直到我們提交 CTA。因此，在接下來的幾個季度中，您可能會開始聽到更多有關新提名的臨床候選人的信息。

For example, yesterday we announced that we filed a CTA for ARO-DM1, our clinical candidate for the treatment of patients with type 1 myotonic dystrophy, or DM1, and our second clinical program using the TRiM platform for delivery to skeletal muscle.

例如，昨天我們宣布，我們為ARO-DM1 提交了CTA，這是我們用於治療1 型強直性肌肉營養不良症（DM1）患者的臨床候選藥物，也是我們使用TRiM 平台輸送至骨骼肌的第二個臨床項目。

The Phase 1/2a dose-escalating study will evaluate the safety, tolerability, and PK/PD profile of single and multiple ascending doses of ARODM1 compared to placebo in up to 48 patients with DM1.

1/2a 期劑量遞增研究將在多達 48 名 DM1 患者中評估單次和多次遞增劑量 ARODM1 與安慰劑相比的安全性、耐受性和 PK/PD 特徵。

ARO-DM1 is designed to reduce expression of the dystrophia myotonica protein kinase or DMPK gene. DM1 is the most common adult-onset muscular dystrophy. And there is currently no approved disease-modifying therapy.

ARO-DM1 旨在減少強直性營養不良蛋白激酶或 DMPK 基因的表達。 DM1 是最常見的成人肌肉營養不良症。目前還沒有核准的疾病緩解療法。

Treatments have focused on symptomatic management, including physical therapy, exercise, anklefoot orthoses, wheelchairs, and other assistive devices. ARO-DM1 represents a novel approach to treat DM1 by silencing aberrantly transcribed DMPK mRNA, which could lead to improvements in multiple symptoms, including muscle strength and function.

治療的重點是症狀管理，包括物理治療、運動、踝足矯正器、輪椅和其他輔助設備。 ARO-DM1 代表了一種透過沉默異常轉錄的 DMPK mRNA 來治療 DM1 的新方法，這可能會改善多種症狀，包括肌肉力量和功能。

We have several exciting early-stage clinical programs that target genes expressed in the liver, lung, muscle, and CNS, each of which is moving toward proof-of-concept data.

我們有幾個令人興奮的早期臨床項目，針對肝臟、肺部、肌肉和中樞神經系統中表達的基因，每個項目都正在朝向概念驗證數據。

However, I will focus on our three pulmonary programs. Specifically, I'd like to review safety and tolerability data to date, recent chronic toxicology results that I think help to de-risk the pulmonary platform broadly, as well as some new PD data that further support our plans to rapidly move all programs forward.

不過，我將重點放在我們的三個肺部項目。具體來說，我想回顧一下迄今為止的安全性和耐受性數據、最近的慢性毒理學結果，我認為這些數據有助於廣泛降低肺部平台的風險，以及一些新的PD 數據，這些數據進一步支持我們快速推進所有專案的計劃。

To review, our 3 clinical stage pulmonary programs are the following: ARO-RAGE is designed to reduce expression of the receptor for advanced glycation end products, or RAGE, as a potential treatment for inflammatory pulmonary diseases.

回顧一下，我們的 3 個臨床階段肺部項目如下： ARO-RAGE 旨在減少晚期糖化終產物受體 (RAGE) 的表達，作為發炎性肺部疾病的潛在治療方法。

ARO-MUC5AC is designed to reduce production of mucin 5AC, or MUC5AC as a potential treatment, for muco-obstructive pulmonary diseases. And ARO-MMP7 is designed to reduce expression of matrix metalloproteinase 7, or MMP7, as a potential treatment for idiopathic pulmonary fibrosis, or IPF.

ARO-MUC5AC 旨在減少黏蛋白 5AC 或 MUC5AC 的產生，作為黏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 (MMP7) 的表達，作為特發性肺纖維化 (IPF) 的潛在治療方法。

All 3 of these programs are in Phase 1/2a clinical trials evaluating single and multiple doses in normal healthy volunteers and in patients. Across the 3 programs, 145 total subjects, both normal healthy volunteers and patients, have received active drug via inhalation, with another 31 receiving ARORAGE via the subcutaneous route.

所有 3 個項目均處於 1/2a 期臨床試驗中，評估正常健康志願者和患者的單劑量和多劑量。在這 3 個項目中，共有 145 名受試者（包括正常健康志願者和患者）透過吸入方式接受了活性藥物，另外 31 名受試者透過皮下途徑接受了 ARORAGE。

There have been no serious adverse events deemed to be related to drug. There have been no patterns of drug related adverse events, pulmonary adverse events such as cough or shortness of breath, or adverse changes in lab or spirometry values. There has also been no evidence of local lung inflammation based on BALF cell count evaluation and all chest X-rays have been read as normal.

沒有發生被認為與藥物有關的嚴重不良事件。沒有與藥物相關的不良事件、肺部不良事件（例如咳嗽或氣短）或實驗室或肺活量測定值的不良變化。根據 BALF 細胞計數評估，也沒有發現局部肺部發炎的證據，所有胸部 X 光檢查均顯示正常。

These safety and tolerability results have largely been consistent across the 3 programs and are highly encouraging for the pulmonary platform.

這些安全性和耐受性結果在 3 個項目中基本一致，對於肺部平台來說非常令人鼓舞。

Next, I'd like to cover the chronic toxicology results for ARO-RAGE and AROMMP7, which we recently received. These results are also highly encouraging and suggest that we have sufficient safety margins to proceed confidently to Phase 2.

接下來，我想介紹我們最近收到的 ARO-RAGE 和 AROMMP7 的慢性毒理學結果。這些結果也非常令人鼓舞，顯示我們有足夠的安全裕度充滿信心地進入第二階段。

Specifically, for ARO-RAGE the no observed adverse effect level, or NOAEL, in the 6-month rat study was the mid dose and in the 9-month monkey study it was the highest dose studied.

具體而言，對於 ARO-RAGE，在 6 個月的大鼠研究中，未觀察到不良反應水平 (NOAEL) 是中等劑量，在 9 個月的猴子研究中，它是所研究的最高劑量。

For ARO-MMP7 the rat NOAEL was the highest dose, and the monkey NOAEL was the mid dose. Keep in mind that dose levels selected for GLP toxicology studies are high multiples of the desired clinical dose, so some findings in a toxicology study are expected.

對於ARO-MMP7，大鼠NOAEL為最高劑量，猴NOAEL為中間劑量。請記住，為 GLP 毒理學研究選擇的劑量水平是所需臨床劑量的高倍數，因此毒理學研究中的一些結果是預期的。

The results for both ARO-RAGE and ARO-MMP7 suggest that the learnings and improvements we have made since our first-generation pulmonary candidate, ARO-ENaC, have improved the therapeutic index for our inhaled siRNA programs.

ARO-RAGE 和 ARO-MMP7 的結果表明，自我們的第一代肺部候選藥物 ARO-ENaC 以來我們所取得的學習和改進已經提高了我們吸入 siRNA 項目的治療指數。

Pending feedback from regulatory authorities, we are confident that we will have the required safety margins to begin Phase 2 studies.

在等待監管機構的回饋之前，我們相信我們將擁有開始第二階段研究所需的安全裕度。

This is an important step for the pulmonary platform at an important time as we look to design and initiate Phase 2 studies in 2024.

這是肺部平台在重要時刻邁出的重要一步，因為我們希望在 2024 年設計並啟動 2 期研究。

Now, moving on to new pharmacodynamic data, ARO-RAGE continues to yield promising dose-dependent target engagement results. We previously reported impressive reductions of soluble RAGE protein, or sRAGE, in serum and in bronchoalveolar lavage fluid, or BALF, in healthy volunteers.

現在，轉向新的藥效學數據，ARO-RAGE 繼續產生有希望的劑量依賴性標靶參與結果。我們先前曾報道健康志願者血清和支氣管肺泡灌洗液（BALF）中可溶性 RAGE 蛋白（sRAGE）顯著減少。

Previously reported at our June Analyst R&D Day, after 2 doses of 92 mg given on Days 1 and 29, serum sRAGE mean maximum reduction was 80% with a maximal knockdown of 90%. After a single dose of 184 mg, we observed a mean reduction of 90% and maximal reduction of 95% in BALF sRAGE, with mean maximum serum sRAGE reduction of 76% and maximal reduction of 91%.

先前在我們的 6 月分析師研發日報道，在第 1 天和第 29 天給予 2 劑 92 mg 後，血清 sRAGE 平均最大降低為 80%，最大敲低為 90%。單劑量 184 mg 後，我們觀察到 BALF sRAGE 平均降低 90%，最大降低 95%，血清 sRAGE 平均最大降低 76%，最大降低 91%。

We have since received additional sRAGE data after 2 doses of 184 mg in healthy volunteers. After a second dose of 184 mg, serum sRAGE mean maximum reduction was 89% with a maximal knockdown of 96%. Additionally reduction of serum sRAGE was similar in healthy volunteers and in patients with asthma at the 44 mg dose level.

此後，我們在健康志願者中接受 2 劑 184 mg 劑量後收到了額外的 sRAGE 數據。第二次 184 mg 劑量後，血清 sRAGE 平均最大降低 89%，最大敲低為 96%。此外，在 44 mg 劑量下，健康志願者和氣喘患者的血清 sRAGE 降低程度相似。

So, what are the next data points that we are watching? We are currently enrolling the top dose cohort in mild-to-moderate asthma patients and have initiated a cohort of asthma patients with high baseline levels of fractional exhaled nitric oxide, or FeNO, which is a biomarker for the degree of IL-13 driven type 2-inflammation in the lung.

那麼，我們接下來關注的數據點是什麼？我們目前正在招募輕度至中度氣喘患者的最高劑量隊列，並啟動了呼氣一氧化氮（FeNO）基線水平較高的氣喘患者隊列，FeNO 是 IL-13 驅動型程度的生物標記2-肺部發炎。

These are both important to watch. If we continue to see consistency of PD effect in asthma patients, that would be encouraging. Also, it would be highly encouraging if RAGE lung knockdown leads to an anti-inflammatory effect, via the FeNO biomarker, in either the mild-to-moderate asthma patient cohorts or, more likely, in the high FeNO cohort. The former should have data available during the coming months and the latter will have data around Q3 of 2024.

這些都很值得關注。如果我們繼續在氣喘患者中看到 PD 效果的一致性，那將是令人鼓舞的。此外，如果 RAGE 肺部敲除透過 FeNO 生物標記在輕至中度氣喘患者群體中或更可能在高 FeNO 群體中產生抗發炎作用，那將是非常令人鼓舞的。前者應該在未來幾個月內提供數據，後者將在 2024 年第三季左右提供數據。

I will now turn the call over to Ken Myszkowski. Ken?

我現在將把電話轉給 Ken Myszkowski。肯？

Thank you, James, and good afternoon everyone. As we reported today, our net loss for fiscal 2023 was $205.3 million or $1.92 per share based on 106.8 million fully-diluted weighted average shares outstanding. This compares with a net loss of $176.1 million or $1.67 per share based on 105.4 million fully-diluted weighted average shares outstanding, for 2022.

謝謝你，詹姆斯，大家下午好。正如我們今天報道的，我們 2023 財年的淨虧損為 2.053 億美元，即每股 1.92 美元，基於 1.068 億股完全稀釋加權平均已發行股票計算。相較之下，2022 年淨虧損為 1.761 億美元，即每股淨虧損 1.67 美元（基於 1.054 億股完全稀釋加權平均已發行股票計算）。

Revenue for fiscal 2023 was $240.7 million, compared to $243.2 million for 2022. Revenue in the current period primarily relates to our collaboration agreements with Takeda, GSK & Amgen. Revenue is recognized as we complete our performance obligations or key developmental milestones are reached.

2023 財年的收入為 2.407 億美元，而 2022 年為 2.432 億美元。本期收入主要與我們與武田 (Takeda)、葛蘭素史克 (GSK) 和安進 (Amgen) 的合作協議有關。當我們完成履約義務或達到關鍵發展里程碑時確認收入。

For Takeda, Revenue is recognized commensurate to our performance obligation, which includes managing the ongoing AAT Phase 2 clinical trials. There remains $866,000 of revenue to be recognized associated with the Takeda collaboration which will be recognized in the next fiscal quarter.

對於武田來說，收入的確認與我們的履約義務相稱，其中包括管理正在進行的 AAT 二期臨床試驗。與武田合作相關的收入仍有 866,000 美元需要確認，該收入將在下一財季確認。

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

上一期間的收入主要與確認從我們與 GSK 的許可和合作協議中收到的付款以及從我們與 Takeda 和 Horizo​​​​n 的許可和合作協議中收到的部分付款有關。

Total operating expenses for fiscal 2023 were $445.7 million, compared to $421.7 million for 2022. This increase is driven primarily by increased candidate specific and discovery R&D costs as the Company's pipeline of clinical candidates has both increased and advanced into later stages of development.

2023 財年的總營運費用為4.457 億美元，而2022 年為4.217 億美元。這一增長主要是由於候選藥物特定和發現研發成本的增加，因為公司的臨床候選藥物管道已增加並進入後期開發階段。

Net cash used by operating activities during fiscal 2023 was $153.9 million, compared with net cash used by operating activities of $136.1 million during 2022. The increase in cash used by operating activities is primarily driven by higher research and development expenses. We expect our operating cash burn to be $110 million to $130 million per quarter in fiscal 2024. And we expect full year capital expenditures of approximately $150 million as we near completion of our GMP manufacturing facility.

2023 財年經營活動使用的現金淨額為 1.539 億美元，而 2022 年營業活動使用的現金淨額為 1.361 億美元。經營活動使用的現金增加主要是由於研發費用增加。我們預計 2024 財年每季的營運現金消耗為 1.1 億至 1.3 億美元。隨著我們的 GMP 製造設施即將竣工，我們預計全年資本支出約為 1.5 億美元。

Turning to our balance sheet, our cash and investments totaled $403.6 million at September 30, 2023, compared to $482.3 million at September 30, 2022. The decrease in our cash and investments was primarily due to cash used for operating activities and capital expenditures, partially offset by cash inflows from financing activities. Our common shares outstanding at September 30, 2023, were 107.3 million.

轉向我們的資產負債表，截至2023 年9 月30 日，我們的現金和投資總額為4.036 億美元，而2022 年9 月30 日為4.823 億美元。我們的現金和投資減少主要是由於用於經營活動和資本支出的現金，部分是由於被融資活動現金流入所抵銷。截至 2023 年 9 月 30 日，我們的已發行普通股為 1.073 億股。

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. Arrowhead had another productive quarter. And we see wide open space to accelerate our growth over the coming year. We expect 2024 to be a data- and event-rich year with many expected opportunities to create value including: readout of the plozasiran FCS Phase 3, filing our first NDA, launching a Phase 3 for sHTG with plozasiran, launching a Phase 3 CVOT with either plozasiran or zodasiran, readout in various patient populations with ARO-C3, initial CNS data in patients with ARO-SOD1, ARO-RAGE FeNO and knockdown data in asthma patients, ARO-MMP7 knock down data in IPF patients, ARO-MUC5AC knock down data in asthma and COPD patients, and initiation of first-in-human studies with our first adipose-targeting candidate.

謝謝，肯。 Arrowhead 又度過了一個富有成效的季度。我們看到了未來一年加速成長的廣闊空間。我們預計2024 年將是數據和事件豐富的一年，預計將有許多創造價值的機會，包括：公佈plozasiran FCS 第3 階段、提交我們的第一份NDA、與plozasiran 啟動sHTG 第3 階段、與plozasiran啟動第3 期CVOT plozasiran 或zodasiran、不同ARO-C3 患者群體的讀數、ARO-SOD1 患者的初始CNS 數據、ARO-RAGE FeNO 和氣喘患者的敲除數據、IPF 患者的ARO-MMP7 敲除數據、ARO -MUC5AC 敲除數據減少氣喘和慢性阻塞性肺病患者的數據，並啟動我們的第一個脂肪靶向候選藥物的首次人體研究。

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) And our first question comes from Edward Tenthoff from Piper Sandler.

（操作員說明）我們的第一個問題來自 Piper Sandler 的 Edward Tenthoff。

I'm excited about all the progress on the cardiovascular side. I wanted to ask about the DM1 filing today because now with this, I think you guys also recently maybe filed on DUX4, if I'm remembering correctly. So this isn't really a franchise you're starting to build in muscle. Is this going to be a core area? Or could this be one of the areas for potential partnership that you were highlighting?

我對心血管的所有進展感到興奮。我今天想問 DM1 備案的問題，因為現在有了這個，我想你們最近也可能在 DUX4 上備案，如果我沒記錯的話。所以這並不是一個真正需要你開始增強實力的特許經營權。這會成為核心區域嗎？或者這可能是您強調的潛在合作領域之一？

And again, we're really sorry for the technical problems. I think you're right. We view skeletal muscle as potentially another vertical, another franchise. We think both DM1 and DUX4 are good targets. We think these are 2 large numbers of patients who desperately need treatment options. And so we're excited about these.

再次，我們對技術問題深表歉意。我想你是對的。我們將骨骼肌視為潛在的另一個垂直領域、另一個專營權。我們認為 DM1 和 DUX4 都是不錯的目標。我們認為這兩大群患者迫切需要治療方案。所以我們對這些感到興奮。

We are looking at some additional targets as well. And so we'll see if this can grow to be something as large as we first see pulmonary being for instance. At this point, it's a little bit too early to tell. But I would agree that right now, it appears to be a pretty interesting burgeoning franchise for us.

我們也在考慮一些額外的目標。因此，我們將看看它是否可以發展到像我們第一次看到的肺部一樣大。現在下結論還為時過早。但我同意，現在這對我們來說似乎是一個非常有趣的新興特許經營權。

And our next question comes from Eliana Merle from UBS.

我們的下一個問題來自瑞銀集團的 Eliana Merle。

All the color on the time lines for the pulmonary programs. Maybe just in terms of understanding the biology of rats, particularly in the high FeNO cohorts. I guess what are you looking to see there? And what would you view as clinically meaningful?

肺部程序時間線上的所有顏色。也許只是為了了解老鼠的生物學，特別是在高 FeNO 群體中。我猜你想在那裡看到什麼？您認為什麼具有臨床意義？

Javier, would you like to start this?

哈維爾，你願意開始嗎？

Sure. You can start first.

當然。你可以先開始。

We would expect to see the reductions in FeNO, primarily based on our animal data. The work we did in the area of model showed steep reductions in IL-13. It can measure FeNO in the rats. But a large reduction in IL-13 should translate into a reduction in FeNO.

主要根據我們的動物數據，我們預計 FeNO 會減少。我們在模型領域所做的工作顯示 IL-13 急劇減少。它可以測量大鼠體內的 FeNO。但 IL-13 的大量減少應該會轉化為 FeNO 的減少。

And in terms of what would be clinically meaningful based on what was seen with tezepelumab or Dupixent. I think something in the 30% or so range would put us in the range of what those other molecules have been able to show.

根據 tezepelumab 或 Dupixent 的觀察結果，了解什麼具有臨床意義。我認為 30% 左右的範圍內的東西將使我們處於其他分子能夠顯示的範圍內。

Javier, is there anything to add?

哈維爾，還有什麼要補充的嗎？

No, I think that's it.

不，我想就是這樣。

And our next question comes from Maurice Raycroft from Jefferies.

我們的下一個問題來自傑富瑞 (Jefferies) 的莫里斯·雷克羅夫特 (Maurice Raycroft)。

I was going to ask one on ARO-RAGE too. You mentioned that in patients, the data is mapping with what you observed in healthy volunteer data. Can you elaborate on whether you're seeing this for your 92 and 184 mg asthma patients? And could you have the FEV1 data from these non-FeNO patients potentially even by year-end or first quarter of next year, I guess, maybe if you could provide more granularity on the time line there?

我也想問一個關於 ARO-RAGE 的問題。您提到，在患者中，數據與您在健康志願者數據中觀察到的數據相對應。您能否詳細說明您是否在服用 92 毫克和 184 毫克的氣喘患者中看到這種情況？我想，您是否可以在明年年底或明年第一季獲得這些非 FeNO 患者的 FEV1 數據，也許您可以提供更詳細的時間軸？

And also, you talked a little bit about the sub-Q ARO-RAGE data. Can you remind -- or can you talk about what you're seeing there and remind what the purpose is of assessing that round of administration?

另外，您也談到了一些有關 sub-Q ARO-RAGE 資料的內容。您能否提醒一下—或者您能否談談您所看到的情況並提醒一下評估該輪行政管理的目的是什麼？

So I'll take those in reverse order. Sub-Q, we're still about halfway through that study. The study is fully enrolled with healthy volunteers over just collecting the data from some of the earlier cohorts. So we're not ready to share the S-RAGE data from those studies yet.

所以我會以相反的順序來處理。 Sub-Q，我們的研究還進行了一半。該研究完全招募了健康志願者，而不僅僅是從一些早期隊列中收集數據。因此，我們還沒有準備好分享這些研究中的 S-RAGE 數據。

The idea there is that based on the animal work we've done, we were able to see significant levels of knockdown in both rodents and in monkeys with sub-Q administration. So we wanted to review that as a potential additional option, an optional route of administration that could be different from an inhaled route of administration.

我們的想法是，根據我們所做的動物研究，我們能夠在囓齒類動物和猴子中看到亞 Q 給藥的顯著水平的擊倒。因此，我們想將其作為潛在的附加選擇進行審查，這是一種可能不同於吸入給藥途徑的可選給藥途徑。

Then, the next question, I think, was on FEV1. We've seen those data as they come in. That's primarily in their safety endpoint and the cohort sizes are very small. We've not analyzed those data in the patient cohort that we have filled at this time.

然後，我認為下一個問題是關於 FEV1 的。我們已經看到了這些數據。這主要是在其安全終點方面，並且隊列規模非常小。我們尚未分析目前填寫的患者群組中的這些數據。

So I think it's too early for us to say anything about FEV1 changes. Suffice it to say that the gold sizes are single digits and FEV1 can be a noisy metric.

所以我認為現在談論 FEV1 變化還為時過早。可以這麼說，黃金尺寸是個位數，FEV1 可能是一個吵雜的指標。

And then the first question was – that's right. Yes. We only have the S-antigen data or the S-RAGE reduction data from the 44 milligram dose level in the patients. So we've not seen the S-RAGE reduction data from 92 milligrams or 184 milligrams.

然後第一個問題是──沒錯。是的。我們只有患者 44 毫克劑量水準的 S 抗原數據或 S-RAGE 減少數據。所以我們還沒有看到 S-RAGE 減少 92 毫克或 184 毫克的數據。

Okay. And for FEV1 at baseline, is that something you can comment on for the asthma cohorts, the higher dose cohorts?

好的。對於基線時的 FEV1，您可以對氣喘組（即高劑量組）進行評論嗎？

Yes. Again, I think we don't have all of the aggregated data as of yet.

是的。同樣，我認為我們目前還沒有所有的匯總數據。

But all the study on mild asthma patients, so it's expected to have cell normal base than it is not the most patient for the FeNO cohorts. I mean the (inaudible) [00:52:13] but in the asthma, they had a mild patient life definition.

但所有研究都是針對輕度氣喘患者，因此預計細胞正常基礎不是 FeNO 隊列中大多數患者的情況。我的意思是（聽不清楚）[00:52:13]，但在氣喘方面，他們有一個溫和的病人生命定義。

So more mild patients in the other patients for those 2 higher dose cohorts?

那麼這兩個較高劑量組的其他患者中有較多輕度患者嗎？

Yes.

是的。

And our next question comes from Mani Foroohar from Leerink Partners.

我們的下一個問題來自 Leerink Partners 的 Mani Foroohar。

I guess I'm going to go out on an ultimately more macro and philosophical question. You talked about sort of monetize some type of synthetic royalty or royalty cell monetization. You talked about a couple of different approaches to finance the ongoing CVOT. That in my mind raised 2 questions.

我想我最終會討論一個更宏觀和哲學的問題。您談到了將某種類型的合成版稅或版稅細胞貨幣化。您談到了為正在進行的 CVOT 提供資金的幾種不同方法。在我看來，這提出了兩個問題。

One that is, by definition, anything that the royalties is a fairly high duration financing instrument and that it's a central reforms embedded debt. How do you think about timing a royalty or I guess, convert any type of rate dependent transaction, given how volatile the funding rates of anyone who would be buying that royalty from you would be.

根據定義，特許權使用費是一種期限相當高的融資工具，並且是一項中央改革嵌入債務。考慮到從您那裡購買特許權使用費的任何人的資金費率會有多大的波動性，您如何考慮收取特許權使用費的時間，或者我猜，轉換任何類型的利率相關交易。

You do want to wait until rates come down to see if you could potentially get a tighter spread, et cetera? Just how do you think of that from a purely financial CFO macro perspective?

您確實想等到利率下降，看看是否有可能獲得更窄的利差，等等？您從純粹的財務財務長宏觀角度如何看待這一點？

And then, secondarily, any I'm going to stop. I'll ask my follow-up afterwards.

其次，我要停止任何事。之後我會詢問我的後續狀況。

Sure. So the short answer is no, we would not wait for macro environments to change. Who knows where they are going to go. There are several funders, multiple funders that do this kind of work.

當然。所以簡短的回答是否定的，我們不會等待宏觀環境改變。誰知道他們要去哪裡。有多位資助者、多位資助者從事此類工作。

And we've been chatting with some of them for a bit now. And we believe that there are -- there could be attractive opportunities there that are not dependent upon fundamental changes in the macro environment. So we feel comfortable that there are – that there is capital there at a reasonable rate for us to finance this in this kind of matter.

我們已經和他們中的一些人聊了一段時間。我們相信，那裡可能存在不依賴宏觀環境根本變化的有吸引力的機會。因此，我們感到放心的是，那裡有合理利率的資本，可以為我們解決此類問題提供資金。

Will we ultimately pull that lever? We haven't made that decision. But we just wanted to make clear that that is a lever and potentially an attractive lever that we could pull as part of an overall financing strategy.

我們最終會拉動這個槓桿嗎？我們還沒有做出這個決定。但我們只是想明確表示，這是一個槓桿，並且可能是一個有吸引力的槓桿，我們可以將其作為整體融資策略的一部分。

And I guess my follow-up is if you're going to be selling part of the economics of an asset that you're going into a CVOT. But how do you think about that versus partnering the asset entirely rather than CVOT yourself. Presumably a large pharma partner would ascribe a lower operational discount to their only carrying out of a CVOT versus you guys doing your first CVOT, implying a more attractive NPV if they were to acquire the asset from you in a partnership, whether 100% purchase, royalty, 50-50, any -- under any terms by definition, the economics of a partnership would be better than doing raising capital during yourself.

我想我的後續行動是，如果你要出售你要進入 CVOT 的資產的部分經濟性。但是，與完全合作資產而不是自己進行 CVOT 相比，您如何看待這一點。據推測，大型製藥合作夥伴將較低的營運折扣歸因於他們僅進行CVOT，而不是你們進行第一次CVOT，這意味著如果他們要透過合作夥伴關係從你們那裡收購資產，無論是100 % 購買，NPV 都會更具吸引力。特許權使用費，50-50，任何——根據定義的任何條款，合夥企業的經濟效益都比自己籌集資金更好。

So how do you -- so is there a reason why you see retaining it and then raising that it implied higher cost of capital as a better strategy rather than selling it at an implied lower or partnering in other side, lower cost of capital and eliminating the operating risk of having to do CVOT yourself.

那麼，您是否有理由認為保留它，然後提高它意味著更高的資本成本作為更好的策略，而不是以隱含的較低價格出售它或與另一方合作，降低資本成本並消除必須自己進行CVOT 的操作風險。

Yes. Look, those are all things that we consider as we look at the array of funding opportunities ahead of us. The paying some amount of royalties on these is relatively cheap for us because we're not stacking royalties. We don't have royalties on any of these assets.

是的。看，這些都是我們在審視眼前的一系列融資機會時所考慮的事情。對我們來說，支付一定數量的特許權使用費相對便宜，因為我們不會疊加特許權使用費。我們不對任何這些資產收取特許權使用費。

And so -- and presumably also those royalties we capped, presumably would not go indefinitely. But you're right. As we look at all these opportunities, we need to take all those things into consideration.

因此，我們設定的特許權使用費可能不會無限期地消失。但你是對的。當我們審視所有這些機會時，我們需要考慮所有這些因素。

Look, we see ourselves as a commercial company. And we think we can create a lot of value as a commercial company. And so assuming that our -- the relative cost of capital while holding on these assets is reasonable, then, that's something that we would do.

看，我們將自己視為一家商業公司。我們認為，作為一家商業公司，我們可以創造很多價值。因此，假設我們持有這些資產時的相對資本成本是合理的，那麼，這就是我們會做的事情。

And our next question comes from David Lebowitz from Citi.

我們的下一個問題來自花旗銀行的 David Lebowitz。

Just key backing on the last question. As far as any licensing agreements you're looking at, are you planning to wait until after the pivotal data? And also, what activity level are you intending to really take within the partnership? Is this something where you're going to be very active licensing to kind of one of these royalty companies? Or would this be something more specific where you're basically going to control of the asset to a larger pharmaceutical player?

只是最後一個問題的關鍵支持。就您正在查看的任何授權協議而言，您是否計劃等到關鍵數據之後？另外，您打算在合作關係中真正採取什麼活動水平？您是否會非常積極地向這些特許權使用費公司之一授予許可？或者這會是更具體的事情，您基本上將控制資產給更大的製藥公司？

Yes. The answer to that would just depend upon the asset, of course. We have done and we'll continue to do asset licenses like we do with HSD or HBV or AAT is a little bit different because we do pose there. But for -- there -- we will do those going forward, depending upon the asset.

是的。當然，這個問題的答案只取決於資產。我們已經完成並將繼續進行資產許可，就像我們對 HSD 或 HBV 或 AAT 所做的那樣，有點不同，因為我們確實在那裡擺姿勢。但對於——在那裡——我們將根據資產繼續進行這些工作。

Look, here's our goal. We have a very large pipeline and it's only going to get larger. And so we've got plenty of room to license out some individual assets. What we want to end up with is a series of verticals where we can concentrate commercial build-out. And we can give our commercial team several drugs to hold in the bag to sell into various channels.

看，這就是我們的目標。我們有一個非常大的管道，而且它只會變得更大。因此，我們有足夠的空間來授權一些個人資產。我們最終想要的是一系列可以集中商業建設的垂直領域。我們可以給我們的商業團隊提供幾種藥物，將其裝在袋子裡，然後銷往各種管道。

I think we can do that given our franchises were pulmonary muscle cardio-metabolic, CMS, et cetera, adipose, et cetera. So I think we can do that. And as we look at how to cluster those, we will find that there are some outliers, if you will, some that may not fit well into a commercial strategy.

我認為我們可以做到這一點，因為我們的專營權包括肺肌肉心臟代謝、CMS 等、脂肪等。所以我認為我們可以做到這一點。當我們研究如何對這些進行聚類時，我們會發現存在一些異常值（如果你願意的話），其中一些可能不太適合商業策略。

And those would be the easy ones. Those would be the easy ones to license out. We also have the opportunity to do platform deals. We talked about this in the past. I like them a lot. We now have 5 platforms, 5 different cell types that we can address. I like the idea of working with partners who can bring in targets to us and we can help to create drugs for those partners.

這些都是簡單的。這些是很容易獲得許可的。我們還有機會進行平台交易。我們過去曾討論過這個問題。我很喜歡他們。我們現在有 5 個平台、5 種不同的細胞類型可供我們處理。我喜歡與能夠為我們帶來目標的合作夥伴合作，我們可以幫助這些合作夥伴生產藥物。

That for me is found value as long as those targets are not what we're working on right now. And so maybe it's an unsatisfying answer because we'll be doing a number of different things, but that's the way we see the waterfront. And again, we are 1 or 2 asset company, then, the answer will be much simpler. But we are a 20-plus asset company. And so we have the ability to structure a number of different partnerships and go-to-market strategies for ourselves.

對我來說，只要這些目標不是我們現在正在努力的目標，那就有價值。所以也許這是一個令人不滿意的答案，因為我們將做許多不同的事情，但這就是我們看待海濱的方式。再說一遍，我們是 1 或 2 家資產公司，那麼，答案就會簡單得多。但我們是一家擁有 20 多家資產的公司。因此，我們有能力為自己建立許多不同的合作夥伴關係和進入市場策略。

And our next question comes from Luca Issi from RBC Capital.

我們的下一個問題來自 RBC Capital 的 Luca Issi。

Congrats on the primaries. I have a quick one, maybe Javier, if I may. I was under the impression that you were planning a cardiovascular outcome trial with APOC3. While it sounds to me that you're now planning cardiovascular comes out either with APOC3 or ANG3. Assuming if that is correct, what drove the change in strategy? Was this informed by conversations with the FDA? And is this related in any sort of form or shape with the numerical worsening in glycemic control that we've seen for APOC3. Any color there much appreciated.

恭喜初選。我有一個快速的，也許是哈維爾，如果可以的話。我的印像是您正在計劃使用 APOC3 進行心血管結果試驗。雖然在我看來，您現在計劃用 APOC3 或 ANG3 推出心血管產品。假設這是正確的，是什麼推動了策略的改變？這是透過與 FDA 的對話得知的嗎？這是否與我們在 APOC3 中看到的血糖控制數值惡化有任何形式或形狀有關？那裡的任何顏色都非常受歡迎。

Well, thank you for that question, really, really important. And I think this highlights how dynamic is the development today and how fast science changing.

嗯，謝謝你提出這個問題，真的非常重要。我認為這凸顯了當今發展的動態以及科學的變化有多快。

If we go back, I would say, 6 to 9 months when we already were thinking and working on a CVOT trial design for plozasiran ARO-APOC3, the focus was triglyceride and the field was focused on triglyceride as a key component of the receivable grade.

如果我們回到 6 到 9 個月，當我們已經在思考和致力於 plozasiran ARO-APOC3 的 CVOT 試驗設計時，重點是甘油三酯，該領域的重點是甘油三酯作為應收等級的關鍵組成部分。

In the last 6 months, I think that focus has changed. And I'm saying in the last 6 months because I don't know if you're calling to the KOL webinar at the American Heart Association, where Dr. Nordestgaard, showed a slide where you see the number of publications and remnant cholesterol as a component of the residual risk in the last 10 years, which was 10 or 25 per year versus thousand in the last 1 year.

在過去 6 個月裡，我認為重點已經改變了。我之所以說過去6 個月，是因為我不知道您是否會打電話參加美國心臟協會的KOL 網路研討會，Nordestgaard 博士在會上展示了一張幻燈片，您可以在其中看到出版物數量和殘餘膽固醇：過去 10 年剩餘風險的組成部分，每年 10 或 25，而過去 1 年為 1000。

That means the change in this field is happening as we see and the understanding that it's not just TG, but its remnant cholesterol. And it's the totality of the atherogenic lipoprotein is the new development.

這意味著這個領域正在發生變化，正如我們所看到的，我們了解到這不僅僅是三酸甘油酯，還有它的殘餘膽固醇。致動脈粥狀硬化脂蛋白整體是新的發展。

And frankly, 6 months ago or 9 months ago, it wasn't a key component of our decision-making. And it is now and it's been in the last 3 months. For now, when you look at the 2 molecules and you focus on the concept of totality of atherogenic lipoproteins not PG or not only because remember for DUX4 has better efficacy in there.

坦白說，6 個月前或 9 個月前，這並不是我們決策的關鍵組成部分。現在是這樣，過去三個月也是這樣。現在，當您查看這 2 個分子時，您會專注於致動脈粥樣硬化脂蛋白整體的概念，而不是 PG，或者不僅僅是因為 DUX4 在那裡具有更好的功效。

But when you look at the totality of atherogenic lipoproteins, it will arrange 3, reduced the cholesterol by 20-plus percent, reduce remnant cholesterol by 80%. So it is substantially different. The population that we should address may not be exactly the same. And that's something that we're thinking and talking to express right now.

但當你觀察到致動脈粥樣硬化脂蛋白的總量時，它會排列成3，將膽固醇降低20%以上，將殘餘膽固醇降低80%。所以它有本質上的不同。我們應該針對的族群可能不完全相同。這就是我們現在正在思考和討論要表達的內容。

So I think we're changing following the science. We did have conversations with some experts. We did not have any conversation about this with the FDA yet. And within the next month or so, we're going to be close to make a decision and start to define our next step from the regulatory perspective and from the clinical trial design perspective.

所以我認為我們正在遵循科學進行改變。我們確實與一些專家進行了交談。我們尚未與 FDA 就此進行任何對話。在接下來的一個月左右的時間裡，我們將接近做出決定，並開始從監管角度和臨床試驗設計的角度確定我們的下一步。

And I don't think this was -- I don't think you were getting towards this. But let me just say our increasing interest in ANG-3 that doesn't reflect a lack of confidence in APOC3. We were moving forward to that forward on that, as you point out, for a CVOT.

我不認為這是——我不認為你正在走向這個。但我想說的是，我們對 ANG-3 的興趣日益濃厚，但這並不反映我們對 APOC3 缺乏信心。正如您所指出的，我們正在朝著 CVOT 方向前進。

But as the science has been moving as Javier said, over the last 6 months, we've had this growing wait a minute moment where we should be looking also at ANG3 just to ensure that we are pushing the best candidate that we can into a specific type of CVOT.

但正如哈維爾所說，科學一直在發展，在過去的6 個月裡，我們已經經歷了這個越來越長的等待時刻，我們也應該關注ANG3，以確保我們正在將最好的候選人推向一個新的領域。 CVOT 的特定類型。

We are still moving as quickly as we can. Obviously, with FCS, we'll be finished with that Phase III, I think, in the second quarter. We'll be starting the sHTG Phase 3 early 2024. Now we've got a little bit of time to figure out where we're going to place our bet with the CVOT.

我們仍在盡可能快地行動。顯然，透過 FCS，我們將在第二季完成第三階段。我們將於 2024 年初開始 sHTG 第 3 階段。現在我們有一點時間來弄清楚我們將在 CVOT 上下注。

And our next question comes from Brendan Smith from TD Cowen.

我們的下一個問題來自 TD Cowen 的 Brendan Smith。

Congrats on the progress. Just a couple of quick ones, if I could. I also want to have a follow-up just on the timing to pulmonary. Is it fair to say we'll see the high-dose RAGE data in asthma patients by Q2 of next year with the high FeNO data in Q3? And then really just any color you can give us on MMP7, maybe when we might see some of that data next year would be great.

祝賀取得的進展。如果可以的話，就幾個快速的。我還想對肺部的時間進行跟進。可以公平地說，我們將在明年第二季看到氣喘患者的高劑量 RAGE 數據，並在第三季看到高 FeNO 數據嗎？然後，您可以在 MMP7 上為我們提供任何顏色，也許明年我們會看到其中的一些數據，那就太好了。

And then quickly, I just want to see if there's any update on the ARO-C3 program? And if there's any plans to put out any data from that next year either.

然後很快，我只想看看 ARO-C3 計劃是否有任何更新？明年是否有計劃發布任何數據。

Sure. James?

當然。詹姆士？

Sure. Yes. The intention would be to release the S-RAGE data from the asthma cohorts. When it becomes available to us, so probably the middle of the first half of next year, I think for the asthma, the high-dose asthma S-RAGE data. And then in terms of FeNO, the high FeNO cohorts, we're looking at Q3 for placebo data in those patients.

當然。是的。目的是發布氣喘隊列的 S-RAGE 數據。當它提供給我們時，可能是明年上半年中旬，我認為對於氣喘，高劑量氣喘 S-RAGE 數據。然後就 FeNO（高 FeNO 隊列）而言，我們正在研究第三季這些患者的安慰劑數據。

And then what side has been a little more challenging to enroll some protocol requirements in there and the requirement of those patients being severe asthmatics. But likely towards the middle of the year for MMP7 data, we still need to enroll the highest dose cohort of those patients.

然後，哪一方在其中登記一些方案要求以及那些患有嚴重氣喘患者的要求更具挑戰性。但可能到今年年中才能獲得 MMP7 數據，我們仍然需要招募這些患者中最高劑量的隊列。

And in terms of C3, we are in the process of enrolling the patient cohorts, the IgA nephropathy patients as well as the C3G patients, so probably the second half of 2024 or peripheral data.

就 C3 而言，我們正在招募患者群組、IgA 腎病患者以及 C3G 患者，因此可能是 2024 年下半年或外圍資料。

And our next question comes from Mayank Mamtani from B. Riley Securities.

我們的下一個問題來自 B. Riley Securities 的 Mayank Mamtani。

So maybe, James, if you could dive a bit deeper on the safety margin difference that you've seen between MOC5 versus rats and the recent preclinical data that we received. And if you're able to comment on how the mail doses for that correlate the top dose that's being tested in the clinic? And maybe a high-level question on like what for MOC5 would be human proof of concept like we -- like investors think about for at a rage in terms of high asthma patients.

所以，詹姆斯，如果您能更深入地了解您所看到的 MOC5 與大鼠之間的安全裕度差異以及我們最近收到的臨床前數據。如果您能評論一下郵件劑量與診所正在測試的最高劑量之間的關係嗎？也許一個高層次的問題是，MOC5 會像我們一樣對人類概念進行證明——就像投資者在憤怒的氣喘患者身上思考的那樣。

Like you just commented it severe asthmatic patients, but what sort of biological signal would be relevant here, given obviously this is more downstream physiology to IL4-IL13.

就像您剛剛評論的那樣，嚴重氣喘患者，但這裡什麼樣的生物訊號是相關的，顯然這是 IL4-IL13 更下游的生理學訊號。

Yes. I think on the last question, it's a bit tough to pin down what's clinically relevant in terms of MOC5 see knockdown since there's not a great correlate out there from other drugs. So I can't give you an exact number on that.

是的。我認為關於最後一個問題，要確定 MOC5 see 擊倒方面的臨床相關性有點困難，因為與其他藥物沒有很大的相關性。所以我無法給你確切的數字。

In terms of the safety margins comparing MMP-7 or RAGE with ENaC, I guess it depends on the dose level. We use a low, mid and high dose level for all of those chronic tox studies in the rats.

就 MMP-7 或 RAGE 與 ENaC 的安全裕度而言，我想這取決於劑量等級。我們對所有這些大鼠慢性毒性研究使用低、中和高劑量水平。

If you compare the cumulative dose given over a 6-month rat study, at the high dose level for RAGE, we had -- there was a sevenfold difference between the high dose level used in ENaC and in RAGE the 4 to 5-fold difference for MMP-7 in the rat, so a significant difference between the total cumulative doses that were administered in those -- with those 2 different molecules.

如果比較一項為期6 個月的大鼠研究中給予的累積劑量，在RAGE 的高劑量水平下，我們發現ENaC 中使用的高劑量水平與RAGE 中使用的高劑量水平之間存在7 倍的差異，即4 至5 倍的差異對於大鼠的 MMP-7，因此使用這 2 種不同分子對大鼠施用的總累積劑量之間存在顯著差異。

And then just on the muscle targeting programs, DUX4 and DM1. Could you just remind us the targeting receptor ligand approach here? And as obviously, you guys know, it's an active field. There are alternative antibody ASO approaches maybe how does sort of your preclinical data informed what you've seen? And maybe related to that, is the plan to secure non-dilutive capital for that no longer a near-term event, Chris or you're just going to be opportunistic, recognizing that there might be some more clinical data coming in from these targets from any of your peers?

然後是肌肉目標計劃，DUX4 和 DM1。您能否提醒我們這裡的標靶受體配體方法？顯然，你們都知道，這是一個活躍的領域。還有其他抗體 ASO 方法，也許您的臨床前數據如何告訴您所看到的？也許與此相關的是，確保非稀釋資本的計劃不再是近期事件，克里斯，或者你只是會機會主義，認識到這些目標可能會帶來更多臨床數據來自你的同齡人嗎？

I'm sorry, I misunderstood the -- what kind of capital and say that again?

抱歉，我誤解了──什麼樣的資本，再說一次？

Yes. I think you had plans for non-dilutive capital at some point, which delayed the DUX4 program. So I'm just curious if you're no longer going to do anything strategically there for the muscle in the near term?

是的。我認為你們在某個時候制定了非稀釋資本計劃，這推遲了 DUX4 計劃。所以我只是好奇你是否在短期內不再為肌肉做任何策略性的事情？

Right. Yes. That ran, of course, for now. We are happy to run the DUX4 as well as DM1 clinical programs. And then -- which did not mean that we will never partner them. But we were exploring. As you know, we're exploring potentially partnering DUXx4. And it just made sense to us to stop those discussions and we are moving ourselves for right now. James, you want to add?

正確的。是的。當然，現在就這樣了。我們很高興運行 DUX4 以及 DM1 臨床專案。然後——這並不意味著我們永遠不會與他們合作。但我們一直在探索。如您所知，我們正在探索 DUXx4 的潛在合作夥伴。對我們來說，停止這些討論是有意義的，我們現在正在採取行動。詹姆斯，你想補充一下嗎？

Sure. And then, on the comparison with the other muscle targeting platforms that are out there. For DM1, we've looked at knockdown in the FeNO and have achieved compared similar knockdown or similar duration of effect with what's been published for, for example, the transfer targeted platforms.

當然。然後，與現有的其他肌肉靶向平台進行比較。對於 DM1，我們研究了 FeNO 中的擊倒，並實現了與已發布的（例如轉移目標平台）類似的擊倒或類似的效果持續時間的比較。

We used the peptide carrying the -- 6 integrin. So it's a different way of getting the siRNA into the cell. I think -- in terms of total drug dosage or dosages should be much lower compared to -- with the transferring conjugates, which, of course, conjugating siRNA to a monoclonal antibody.

我們使用攜帶-6整合素的勝肽。所以這是一種將 siRNA 引入細胞的不同方法。我認為，就總藥物劑量而言，與轉移綴合物相比，劑量應該低得多，當然，轉移綴合物將 siRNA 與單株抗體綴合。

And then, I'd also anticipate that we would not expect to see some of the transferrin-related safety issues that have been out there. Of course, the time will tell and the data will tell us. But something we would not anticipate.

然後，我還預計我們不會看到一些與轉鐵蛋白相關的安全問題。當然，時間會告訴我們答案，數據會告訴我們答案。但這是我們無法預料到的。

And our next question comes from Patrick Trucchio from H.C. Wainwright and Company.

我們的下一個問題來自 H.C. 的 Patrick Trucchio。溫賴特公司。

Just regarding the 20 in 25 targeted goals, can you give us a sense of from which platforms the 20 drug candidates are expected to emerge from understanding several have been announced this year. And if along with CNS pulmonary liver adipose and muscle of additional tissues may be targeted with TRIM.

僅就 25 個目標中的 20 個目標而言，您能否讓我們了解今年已宣布的 20 種候選藥物預計將從哪些平台出現？如果連同中樞神經系統、肺、肝、脂肪和肌肉等其他組織可能會成為 TRIM 的目標。

I don't have any guidance to tell you on additional cell types other than the fact that we will be in new cell types. We've said publicly that we think we can get into a new cell like every 18 to 24 months. I think that continues.

除了我們將使用新的細胞類型之外，我沒有任何關於其他細胞類型的指導。我們公開表示，我們認為我們可以每隔 18 到 24 個月進入一個新牢房。我認為這種情況仍在繼續。

Look, I expect by the year 2025, we will have new or additional candidates in every one of those verticals.

我預計到 2025 年，我們將在每個垂直領域都有新的或更多的候選人。

And then just a few follow-ups on the pulmonary compounds. Just first, regarding initial chronic tox results to the ARO-RAGE and ARO-MMP 7. I'm wondering if you can tell us if or when further chronic tox data is expected and the level of confidence that data should continue to support advancement of those programs.

然後對肺部化合物進行一些後續檢查。首先，關於 ARO-RAGE 和 ARO-MMP 7 的初步慢性毒性結果。我想知道您是否可以告訴我們是否或何時預計會獲得進一步的慢性毒性數據，以及數據應繼續支持進展的信心程度那些程序。

And when you might have similar data for ARO5AC in 2024? And just a follow-up on ARO-RAGE, if you can discuss the targeting mechanism of the SUB-Q administration and advantages that would be expected for this route relative to the inhaled route.

2024 年什麼時候可以獲得 ARO5AC 的類似數據？這只是 ARO-RAGE 的後續行動，如果您能討論 SUB-Q 給藥的標靶機制以及該途徑相對於吸入途徑的預期優勢。

Yes, sure. So in terms of the chronic rat or the chronic tox data for the pulmonary program, that's it. I mean that's the final report. So there's, no more expectations. We won't be getting any more data around chronic tox for MMP-7 or RAGE.

是的，當然。因此，就慢性大鼠或肺部程序的慢性毒性數據而言，就是這樣。我的意思是這就是最終報告。所以，沒有更多的期望。我們不會獲得更多有關 MMP-7 或 RAGE 慢性毒性的數據。

For MOC5AC, we're still planning the chronic tox study. We wanted to get some biomarker data from the clinical study to better inform on the dose frequency for the chronic tox study since frequency of administration seems to be really important to avoid entering into dose levels where we see toxicity.

對於 MOC5AC，我們仍在計劃慢性毒性研究。我們希望從臨床研究中獲得一些生物標記數據，以便更好地了解慢性毒性研究的劑量頻率，因為給藥頻率對於避免進入我們看到毒性的劑量水平似乎非常重要。

We really wanted to nail down dose frequency. So we need to get duration of effect from the clinical studies before we finalize the chronic tox study for MOC5AC.

我們確實想確定劑量頻率。因此，在最終確定 MOC5AC 的慢性毒性研究之前，我們需要從臨床研究中了解效果的持續時間。

And regarding on the Sub-Q, our thinking there was 201. There could be other targets and other indications where Sub-Q administration is just preferred to inhale.

關於 Sub-Q，我們的想法有 201。可能還有其他目標和其他跡象，其中 Sub-Q 管理更傾向於吸入。

And second, it could -- that could potentially also broaden widen out our therapeutic index.

其次，它可能——這也可能擴大我們的治療指數。

And our next question comes from Prakhar Agrawal from Cantor Fitzgerald.

我們的下一個問題來自 Cantor Fitzgerald 的 Prakhar Agrawal。

Congrats on the progress. So on your ARO-X DH program that was partnered with Horizon. It seems that Amgen has decided to terminate this agreement. Was there any data generated by the DH program? Or was it just part of the recent strategic overall by Amgen after Horizon deal closed? And what are your plans for this asset now develop internally? Or will you be looking for a partner again?

祝賀取得的進展。因此，關於與 Horizo​​​​n 合作的 ARO-X DH 計劃。看來安進已經決定終止這項協議。 DH程式有產生任何資料嗎？或者這只是 Horizo​​​​n 交易完成後安進近期整體戰略的一部分？您現在對該資產的內部開發計劃是什麼？或者你會再尋找合作夥伴嗎？

So it's early to say on that. We haven't seen data. I don't know that we will. But at least so far, we haven't seen any of the clinical data. And so we've not been told why that was being discontinued and whether it's strategic or something else. We have some theories. James, do you want to talk about the Amgen program for instance?

所以現在說這個還太早。我們還沒有看到數據。我不知道我們會的。但至少到目前為止，我們還沒有看到任何臨床數據。因此，我們沒有被告知為什麼要停止該功能，以及這是策略性的還是其他原因。我們有一些理論。詹姆斯，您想談談安進計畫嗎？

Sure. Yes. I think another company had siRNA targeting the same target XPA. It was also discontinued due to lack of decline in uric acid in the blood. But even if you knock down all the SPH in the liver, there are still hepatic sources, so liver knockdown might not have been enough.

當然。是的。我認為另一家公司有針對相同目標 XPA 的 siRNA。由於血液中的尿酸沒有下降，它也被終止。但即使你敲低肝臟中的所有 SPH，仍然存在肝臟來源，因此肝臟敲低可能還不夠。

Our next question comes from Michael Ulz from Morgan Stanley.

我們的下一個問題來自摩根士丹利的邁克爾·烏爾茲。

Maybe just a quick one on ARO-RAGE. Just in terms of timing of a potential Phase 2 study there, now that the chronic tox studies are done for ARO-RAGE, do you have enough data to now start to engage with the FDA? Or is the plan more to wait for some of the other cohort data like the asthma patients or the high FeNO before you start to do that?

也許只是關於 ARO-RAGE 的快速介紹。就潛在的 2 期研究的時間安排而言，現在 ARO-RAGE 的慢性毒性研究已經完成，您是否有足夠的數據可以開始與 FDA 合作？還是計劃更多地等待一些其他隊列數據，例如氣喘患者或高 FeNO，然後再開始這樣做？

We're thinking about starting the study in 2024, for sure, and there's already were going into that aides, patient populations, selection of CRO. So we are already planning as the data is coming in. It will help us to decide to the dose frequency. But we're already planning on the next phase development for the ARO-RAGE.

當然，我們正在考慮在 2024 年開始這項研究，並且已經開始研究助手、患者群體和 CRO 的選擇。因此，隨著數據的到來，我們已經在計劃。這將幫助我們決定劑量頻率。但我們已經在計劃 ARO-RAGE 的下一階段開發。

And our next question comes from William Pickering from Bernstein.

我們的下一個問題來自伯恩斯坦的威廉·皮克林。

I had a few follow-ups on the DM1 announcement. So how is the drug designed to get your siRNA inside the nucleus where the mRNA is accumulating? And maybe can you share any more color on what endpoints will be measuring that could suggest early signs of efficacy, for example, splicing assessment or any functional end points?

我對 DM1 公告進行了一些跟進。那麼，該藥物是如何設計的，可以讓 siRNA 進入 mRNA 累積的細胞核內呢？也許您可以分享更多關於將測量哪些終點的顏色，這些終點可以表明功效的早期跡象，例如剪接評估或任何功能終點？

Sure. Yes. So we will look at some of the same endpoints that other companies have looked at. And we'll look at total DMPK knockdown, changes in (inaudible) [00:79:22]. And we'll also look at the video and opening time as well as some of the other functional endpoints.

當然。是的。因此，我們將研究其他公司研究過的一些相同端點。我們將觀察 DMPK 的整體敲低以及（聽不清楚）[00:79:22] 的變化。我們還將查看視訊和開放時間以及其他一些功能端點。

And so your other question on knocking down siRNA in the nucleus. We've done some work in animals. We haven't published this yet or sorted publicly via poster presentation. But we've shown at doses similar to what we planned on administering in the clinic that we are able to get a level of knockdown of nuclear RNA and that translates into improvements.

那麼你的另一個問題是關於敲除細胞核中的 siRNA。我們在動物身上做了一些工作。我們尚未發布此內容或透過海報演示公開排序。但我們已經證明，在與我們計劃在臨床上使用的劑量相似的情況下，我們能夠實現一定程度的核 RNA 敲低，並轉化為改善。

So that was the impetus for us moving this program into the clinic that we could get even with some modest levels of nuclear RNA knockdown you could get improvements in spisopathy.

因此，這就是我們將該計畫推向臨床的動力，即使進行一定程度的核 RNA 敲低，也可以改善運動病。

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

現在我想將電話轉回克里斯安札龍 (Chris Anzalone) 發表結束語。

Thanks very much, everyone, for joining us today. And I wish you all a happy holiday season.

非常感謝大家今天加入我們。祝大家節日快樂。

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

今天的電話會議到此結束。感謝您的參與。您現在可以斷開連線。