Arrowhead Pharmaceuticals Inc (ARWR) 2023 Q3 法說會逐字稿

Ladies and gentlemen, welcome to the Arrowhead Pharmaceuticals Conference Call. (Operator Instructions)

女士們、先生們，歡迎參加 Arrowhead Pharmaceuticals 電話會議。 （操作員說明）

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

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

Thank you, Stephen. Good afternoon, and thank you for joining us today to discuss Arrowhead's results for its fiscal 2023 third quarter ended June 30, 2023.

謝謝你，斯蒂芬。下午好，感謝您今天加入我們討論 Arrowhead 截至 2023 年 6 月 30 日的 2023 財年第三季度業績。

With us today from management are President and CEO, Dr. Chris Anzalone, who will provide an overview of the quarter; Dr. 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, 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.

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，他將概述本季度的情況；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信息；我們的發現與轉化醫學主管 James Hamilton 博士，他將提供我們早期項目的最新信息；我們的首席財務官 Ken Myszkowski 將對財務狀況進行審查。

In addition, Tracy Oliver, our Chief Commercial Officer and Patrick O’Brien, our Chief Operating Officer and General Counsel, will both be available during the Q&A portion of the call.

此外，我們的首席商務官特雷西·奧利弗（Tracy Oliver）和我們的首席運營官兼總法律顧問帕特里克·奧布萊恩（Patrick O'Brien）都將出席電話會議的問答部分。

Before we begin, I would like to remind you that, comments made during today’s call contain certain forward-looking statements within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934.

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 27A 條和《證券交易》第 21E 條含義內的某些前瞻性陳述1934 年法案。

All statements other than statements of historical fact are forward-looking statements and are subject to numerous risks and uncertainties that could cause actual results to differ materially from those expressed in any forward-looking statements. For further details concerning these risks and uncertainties, please refer to our SEC filings, including our most recent annual report on Form 10-K and our quarterly reports on Form 10-Q.

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，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，包括我們最新的 10-K 表年度報告和 10-Q 表季度報告。

I'd now like to turn the call over to Chris Anzalone, President and CEO of the company. Chris?

我現在想將電話轉給公司總裁兼首席執行官 Chris Anzalone。克里斯？

Thanks, Vince. Good afternoon, everyone and thank you for joining us today. Our industry is built on promise. Sometimes this promise can be stunning and carry with it the possibility of saving the lives of some and drastically improving life for others. Arrowhead's mission is to bring important new medicines to the people who need them, and save lives and alleviate suffering where we can. While this is our guiding principle and focusing on this promise has given us purpose and the motivation to, I believe, innovate at industry-leading levels and operate at speeds not seen before, it is not the only important focus for us.

謝謝，文斯。大家下午好，感謝您今天加入我們。我們的行業是建立在承諾之上的。有時，這種承諾可能令人震驚，並有可能拯救一些人的生命並極大地改善其他人的生活。 Arrowhead 的使命是為有需要的人提供重要的新藥，並儘我們所能拯救生命並減輕痛苦。雖然這是我們的指導原則，並且專注於這一承諾給了我們目標和動力，我相信，以行業領先的水平進行創新並以前所未有的速度運營，但這並不是我們唯一重要的關注點。

Another is risk. Our industry swims in a sea of risk. We recognize that in order to succeed, we need to appreciate the great promise in front of us, but focus on all the risks between the idea and the medicine ultimately given to a patient. We are idealists, but we are not naive. One of our most important jobs is to mitigate and decrease risk where we can. We have made great progress on this broad front since our last call, and this is how I would like to frame our discussion today.

另一個是風險。我們的行業在風險的海洋中游泳。我們認識到，為了取得成功，我們需要欣賞擺在我們面前的巨大希望，但要關注想法和最終給予患者的藥物之間的所有風險。我們是理想主義者，但我們並不天真。我們最重要的工作之一是盡可能減輕和降低風險。自上次通話以來，我們在這一廣泛領域取得了巨大進展，這就是我今天的討論框架。

Let's begin with pulmonary. We believe we've taken an important step toward further de-risking the entire pulmonary franchise with the first chronic GLP toxicology results starting to come in.

我們先從肺部開始。我們相信，隨著第一個慢性 GLP 毒理學結果的開始出現，我們已經朝著進一步降低整個肺部疾病風險邁出了重要一步。

For ARO-MMP7, the NOAEL, or no-observed-adverse-effect level, was the highest dose we tested in our chronic rat study. In other words, even at the highest dose tested, we are not seeing anything that is deemed adverse. The highest dose represents what we believe would be substantially greater exposure than would be applied to humans. We are waiting for final rat data from the ARO-RAGE chronic GLP tox study, but that also is looking like the NOAEL will be the highest dose we tested.

對於 ARO-MMP7，NOAEL（未觀察到不良反應水平）是我們在慢性大鼠研究中測試的最高劑量。換句話說，即使在測試的最高劑量下，我們也沒有看到任何被認為不利的情況。我們認為最高劑量代表的暴露量比應用於人類的暴露量要大得多。我們正在等待 ARO-RAGE 慢性 GLP 毒性研究的最終大鼠數據，但這看起來 NOAEL 將是我們測試的最高劑量。

We are still waiting for the 9-month monkey data in both candidates, but our experience with ARO- ENAC leads us to believe that the rat is the more sensitive species for these pulmonary tox studies. So it is very encouraging to us that the rodent studies look so positive. This is potentially a big step forward for the platform.

我們仍在等待這兩種候選藥物的 9 個月猴子數據，但我們使用 AROENAC 的經驗使我們相信，對於這些肺毒性研究，大鼠是更敏感的物種。因此，囓齒動物研究看起來如此積極，這對我們來說非常令人鼓舞。這可能是該平台向前邁出的一大步。

As you may recall, we saw lung inflammation in some of the chronic GLP tox doses for ARO- ENAC in 2021. Based on our analysis of those results, we concluded that we needed to increase the potency of our pulmonary candidates, and we clearly did that with ARO-MMB7, ARO-RAGE, and ARO-MUC5AC. We were optimistic that these improvements would translate into better chronic tox results, but of course, we couldn't know until the data came in.

您可能還記得，我們在2021 年AROENAC 的一些慢性GLP 毒素劑量中發現了肺部炎症。根據我們對這些結果的分析，我們得出的結論是，我們需要提高肺部候選藥物的效力，而且我們顯然做到了與 ARO-MMB7、ARO-RAGE 和 ARO-MUC5AC 相同。我們樂觀地認為這些改進將轉化為更好的慢性毒性結果，但當然，直到數據到來之前我們無法知道。

As we are now seeing preliminary data from those studies come in, we are increasingly confident that ARO-MMB7 and likely ARO-RAGE may have substantially wider tox windows than ARO-ENAC did. And I believe this represents a significant de-risking event for the pulmonary franchise.

由於我們現在看到這些研究的初步數據，我們越來越有信心 ARO-MMB7 和可能的 ARO-RAGE 可能比 ARO-ENAC 具有更寬的毒性窗口。我相信這對於肺部特許經營來說是一次重大的去風險事件。

We look forward to having a complete rat and monkey chronic GLP tox data for ARO-RAGE and ARO-MMB7 in coming months and expect to have chronic GLP tox data for ARO-MUC5AC next year.

我們期待在未來幾個月內獲得 ARO-RAGE 和 ARO-MMB7 的完整大鼠和猴子慢性 GLP 毒性數據，並預計明年獲得 ARO-MUC5AC 的慢性 GLP 毒性數據。

Encouraging preliminary chronic GLP tox data follow prior de-risking events in the pulmonary franchise over the past quarter. Specifically, I believe the ARO-RAGE clinical data indicate 3 important things; first, the safety and tolerability reports to-date have been good and nothing surprising has emerged. This is always a critical first step for a new platform and every new drug.

令人鼓舞的初步慢性 GLP 毒性數據是在過去一個季度肺部特許經營權的去風險事件之後得出的。具體來說，我認為 ARO-RAGE 臨床數據表明了 3 件重要的事情：首先，迄今為止的安全性和耐受性報告都很好，沒有出現任何令人驚訝的情況。對於新平台和每種新藥來說，這始終是關鍵的第一步。

Second, the activity data we have seen thus far have been impressive and showed continued dose response through the top dose level. After a single inhaled dose of 184 milligrams of ARO-RAGE, we saw up to 95% knockdown with a mean of 90% in that cohort.

其次，我們迄今為止看到的活動數據令人印象深刻，並且顯示出在最高劑量水平下持續的劑量反應。單次吸入 184 毫克 ARO-RAGE 後，我們發現該隊列的基因敲除率高達 95%，平均為 90%。

Not only is this a high level of target gene knockdown that was extraordinarily consistent across participants in the cohort. Each subject had a good response. This is in the same ballpark as what we now expect with optimized liver-targeted programs, and this is an important point.

這不僅是一種高水平的靶基因敲低，而且在隊列參與者中非常一致。每個科目都獲得了良好的反響。這與我們現在對優化肝臟靶向計劃的期望大致相同，這是重要的一點。

I think it is generally accepted that RNAi is a reliable modality to safely reduce expression of a target gene and that when Arrowhead introduces a new liver program, there is high expectation both internally and externally, that the drug candidate will reduce expression of the target protein as designed.

我認為人們普遍認為 RNAi 是一種安全降低目標基因表達的可靠方式，並且當 Arrowhead 推出新的肝臟計劃時，內部和外部都對候選藥物將降低目標蛋白的表達抱有很高的期望按設計。

I am hopeful that each new data set we are approaching with -- I'm sorry, I am hopeful that with each new data set that we are approaching this expectation in pulmonary. That is a giant leap forward and an important value inflection point.

我對我們正在接近的每一個新數據集都充滿希望——對不起，我希望我們在肺部的每一個新數據集上都接近這一期望。這是一個巨大的飛躍，也是一個重要的價值拐點。

Lastly, we think the data also shows that the duration of effect with ARO-RAGE supports a dosing interval of 2 months or more. This is an important de-risking event because it limits accumulated drug exposure, increasing our confidence that the good safety profile seen thus far may continue during chronic treatment. It would also be a very patient-friendly dosing regimen.

最後，我們認為數據還表明 ARO-RAGE 的效果持續時間支持 2 個月或更長的給藥間隔。這是一個重要的去風險事件，因為它限制了累積的藥物暴露，增強了我們的信心，即在長期治療過程中，迄今為止所見的良好安全性可能會持續下去。這也是一種對患者非常友好的給藥方案。

De-risking the pulmonary platform is important for its own sake. As we have said in the past, we see many potential drugs coming out of the franchise that could address a number of unmet medical needs, and we appear to be the only company able to effectively use RNAi in the lungs.

降低肺部平台的風險本身就很重要。正如我們過去所說，我們看到許多潛在的藥物正在湧現，可以解決許多未滿足的醫療需求，而且我們似乎是唯一一家能夠在肺部有效使用 RNAi 的公司。

The pulmonary franchise alone could be the basis of a large company. But it is also important as an example of how we seek to de-risk our broader business. From our perspective, a 1 or 2 drug company is a bet, not a business. From the beginning, we have sought to create a broadly diversified business to increase the number of patients we serve, but also, importantly, as a hedge against the unpredictability of biology.

僅肺部特許經營權就可以成為一家大公司的基礎。但這也是我們如何尋求降低更廣泛業務風險的一個例子，這一點也很重要。從我們的角度來看，一兩個製藥公司是一個賭注，而不是一個生意。從一開始，我們就致力於創建廣泛多元化的業務，以增加我們服務的患者數量，但更重要的是，作為對生物學不可預測性的對沖。

In our industry, the risk of failure is substantial, and our mitigation strategy has been part innovation and part brute force. We have sought to create a technological platform that works reliably and then move as fast as we can to create as many well-thought-out drug candidates as possible. We built and continue to refine and expand the reach of our TRiM platform. This is a modular, structurally simple system to, 1, address multiple cell types, which allows our therapies to go where a disease is in a way that other RNA companies do not; 2, move rapidly from idea to the clinic, and then efficiently through mid- and late-stage clinical studies; and 3, provide platform continuity and competence, which gives us an enhanced expectation of success for new candidates that we believe far exceeds that of biotech broadly.

在我們的行業中，失敗的風險很大，我們的緩解策略部分是創新，部分是暴力。我們一直致力於創建一個可靠運行的技術平台，然後儘可能快地開發出盡可能多的經過深思熟慮的候選藥物。我們建立並繼續完善和擴大 TRiM 平台的覆蓋範圍。這是一個模塊化、結構簡單的系統，1、解決多種細胞類型問題，這使得我們的療法能夠以其他 RNA 公司無法做到的方式針對疾病所在； 2、從想法快速走向臨床，然後高效地進行中後期臨床研究； 3、提供平台的連續性和能力，這使我們對新候選人的成功期望更高，我們認為這遠遠超過了生物技術領域的廣泛成功。

Lessons learned developing each candidate informs the development of future candidates, so our expectation of success grows stronger over time. We believe this translates to the potential for more candidates to become approved therapies than industry average.

培養每位候選人的經驗教訓將為未來候選人的發展提供信息，因此我們對成功的期望隨著時間的推移而變得越來越強烈。我們相信，這意味著有可能比行業平均水平有更多的候選藥物獲得批准。

Our 20 in 2025 initiative follows this platform development and represents, to some extent, the brute force component of our broader risk mitigation strategy. We have platforms that appear to work well, so we have the responsibility to our patients and stakeholders to build as many new drugs as fast as we can. It is our goal to have 20 clinical stage or marketed products by the year 2025.

我們的 2025 年 20 計劃遵循該平台的開發，在某種程度上代表了我們更廣泛的風險緩解策略的強力組成部分。我們擁有運行良好的平台，因此我們對患者和利益相關者有責任盡快開發盡可能多的新藥。我們的目標是到2025年擁有20個臨床階段或上市產品。

Somewhat paradoxically, building such a large pipeline is part of our strategy to mitigate balance sheet risk. We are in a very expensive business, and one could argue that the best way to ensure we are properly capitalized to bring drugs to market is to have a small, focused pipeline. We reject that. Rather, we believe that well-thought-out drug candidates with greater than industry average chances of success can always find homes in partner companies' pipelines.

有點矛盾的是，建設如此龐大的管道是我們減輕資產負債表風險戰略的一部分。我們從事的是一項非常昂貴的業務，有人可能會說，確保我們有適當的資本將藥品推向市場的最佳方法是擁有一個小型的、集中的管道。我們拒絕這一點。相反，我們相信，經過深思熟慮、成功機會高於行業平均水平的候選藥物總能在合作夥伴公司的研發管線中找到立足之地。

As we mentioned at our Analyst Day in June, we have brought in nearly $1 billion in partnering capital over the past 6 years and have not raised equity capital for over 3.5 years. In fact, GSK recently initiated a Phase 2b study of GSK4532990, formerly called ARO-HSD, for the treatment of NASH, which earned us a $30 million milestone payment.

正如我們在 6 月份的分析師日上提到的，我們在過去 6 年裡引入了近 10 億美元的合作資本，並且已經超過 3.5 年沒有籌集股本資本。事實上，GSK 最近啟動了 GSK4532990（以前稱為 ARO-HSD）的 2b 期研究，用於治療 NASH，這為我們贏得了 3000 萬美元的里程碑付款。

In addition, Takeda initiated the Phase 3 Redwood study of Fazirsiran, being developed as a potential treatment for alpha-1 antitrypsin deficiency liver disease, which earned Arrowhead a $40 million milestone payment. We believe that partnering is a good cornerstone of a broader financing strategy and one that our platforms are uniquely suited for because of the quality of the candidates coming out of them and the scarcity of the companies that are skilled at generating RNAi-based therapeutics.

此外，武田啟動了 Fazirsiran 的 3 期 Redwood 研究，該研究被開發為 α-1 抗胰蛋白酶缺乏性肝病的潛在治療方法，這為 Arrowhead 贏得了 4000 萬美元的里程碑付款。我們相信，合作是更廣泛的融資戰略的良好基石，我們的平台非常適合這一戰略，因為這些平台候選人的質量很高，而且缺乏擅長產生基於 RNAi 的療法的公司。

Our partnering strategy includes existing partnerships that are maturing, and therefore, eliciting higher payments, new potential partnerships that could combine our platforms with a partner's target or set of targets, and new partnerships on existing programs in our pipeline.

我們的合作戰略包括正在成熟的現有合作夥伴關係，因此可以帶來更高的付款，可以將我們的平台與合作夥伴的目標或一組目標結合起來的新的潛在合作夥伴關係，以及我們管道中現有項目的新合作夥伴關係。

Regarding the latter on our last earnings call, I discussed that at the time we had paused the CTA filing, because of some inbound interest in partnering ARO-DUX4. We continue to explore those options. However, we decided to move forward with the ARO-DUX4 CTA filing ourselves.

關於後者，在我們上次的財報電話會議上，我討論了當時我們暫停了 CTA 備案，因為有一些對與 ARO-DUX4 合作的興趣。我們將繼續探索這些選擇。然而，我們決定自行推進 ARO-DUX4 CTA 備案。

Partnering discussions can take time, and we don't ultimately know if they will translate into license agreements. We felt it did not make sense to further delay the CTA filing in the Phase 1 study. While partnering continues to be a cornerstone of our financing model, we are certainly cognizant of the risk of over partnering. We believe the best way to build a lot of value quickly is to retain some wholly-owned candidates and drive toward commercialization.

合作討論可能需要時間，而且我們最終不知道它們是否會轉化為許可協議。我們認為在第一階段研究中進一步推遲 CTA 申報沒有意義。雖然合作仍然是我們融資模式的基石，但我們當然認識到過度合作的風險。我們相信，快速創造大量價值的最佳方式是保留一些全資候選人並推動商業化。

Of course, there is substantial risk with this course, but over the past quarter, we believe we have taken some off the table. We completed enrollment in the Phase 3 PALISADE study of ARO-APOC3 in patients with familial chylomicronemia syndrome, or FCS. This is an important milestone for Arrowhead, because it will likely be the first candidate and indication that we will seek regulatory approval for. The final study visit for the last patient in is scheduled for Q2 of 2024, so we expect to start the NDA process next year.

當然，這一過程存在很大的風險，但在過去的一個季度，我們相信我們已經消除了一些風險。我們完成了針對家族性乳糜微粒血症綜合徵 (FCS) 患者的 ARO-APOC3 3 期 PALISADE 研究的入組。這對 Arrowhead 來說是一個重要的里程碑，因為它可能是第一個候選者，也表明我們將尋求監管部門的批准。最後一名患者的最終研究訪視計劃於 2024 年第二季度進行，因此我們預計明年開始 NDA 流程。

In addition to FCS, we are currently working on the Phase 3 plans for severe hypertriglyceridemia and mixed dyslipidemia, which we will be discussing with regulators this year. Shortly after those discussions, we plan to start Phase 3 studies for those larger indications.

除了FCS之外，我們目前正在製定針對嚴重高甘油三酯血症和混合性血脂異常的第三階段計劃，我們將在今年與監管機構討論。在這些討論之後不久，我們計劃開始針對這些更大的適應症的第三階段研究。

Our other wholly-owned cardiometabolic candidates, ARO-ANG3 also had an important milestone during the quarter. We presented data at the European Atherosclerosis Society Congress demonstrating that ARO-ANG3 achieved LDL-C reductions of 44% to 48% when added to existing standard of care treatments. These results are similar to results seen in studies of an approved monoclonal antibody targeting ANGPTL3 in patients with HoFH. These are important derisking data, as we move toward 1 or more Phase 3 programs, which we are currently designing.

我們的其他全資心臟代謝候選藥物 ARO-ANG3 在本季度也取得了重要的里程碑。我們在歐洲動脈粥樣硬化協會大會上提交的數據表明，當添加到現有標準護理治療中時，ARO-ANG3 實現了 LDL-C 降低 44% 至 48%。這些結果與在 HoFH 患者中針對 ANGPTL3 的已批准單克隆抗體的研究結果相似。當我們朝著目前正在設計的 1 個或多個第 3 階段計劃邁進時，這些都是重要的去風險數據。

We are actively working on go-to-market strategies for multiple candidates. We expect to have 4 drug candidates in Phase 3 studies by the end of the year. Two of these are currently wholly-owned, ARO-APOC3 and ARO-ANG3; and third, fazirsiran, is partnered with a 50-50 profit share in the U.S., so we have retained substantial economics.

我們正在積極為多個候選人制定進入市場的策略。我們預計到今年年底將有 4 種候選藥物進入 3 期研究。其中兩個目前為全資擁有，ARO-APOC3 和 ARO-ANG3；第三，fazirsiran，在美國有50-50的利潤分成，所以我們保留了可觀的經濟效益。

As I mentioned, we will have our first Phase 3 registrational study readout mid next year for our APOC3 -- our ARO-APOC3 program in FCS and expect an NDA soon thereafter. As we look at our pipeline, we expect additional NDA filing opportunities on a very regular basis going forward.

正如我提到的，我們將於明年年中公佈 APOC3（FCS 中的 ARO-APOC3 項目）的第一個 3 期註冊研究結果，並預計此後不久將獲得 NDA。當我們審視我們的管道時，我們預計未來會定期有更多 NDA 申請機會。

Moving to our earlier-stage pipeline. We filed 2 CTAs for 2 new programs targeting gene expression in 2 different tissue types. I already mentioned ARO-DUX4 and skeletal muscle for the treatment of FSHD, and the other is ARO-SOD1 in the central nervous system for the treatment of ALS. We expect additional CTAs over the next few quarters using both the CNS and skeletal muscle platforms.

轉向我們的早期階段管道。我們為 2 個針對 2 種不同組織類型中基因表達的新項目提交了 2 個 CTA。我已經提到ARO-DUX4和骨骼肌用於治療FSHD，另一個是ARO-SOD1在中樞神經系統用於治療ALS。我們預計在接下來的幾個季度中將使用中樞神經系統和骨骼肌平台進行更多的 CTA。

Of course, these are early, but they represent important derisking events for potential CNS and skeletal muscle franchises. As with our advances in pulmonary, these are also illustrative of our desire to expand the reach of our technology and decrease the overall risk of our business by creating value across many different channels.

當然，這些還為時過早，但它們代表了潛在中樞神經系統和骨骼肌特許經營權的重要去風險事件。與我們在肺部領域的進步一樣，這些也說明了我們希望通過在許多不同渠道創造價值來擴大我們的技術範圍並降低我們業務的整體風險。

Lastly, before I hand the all over to Javier, I want to highlight the R&D Day that we hosted in June. During that presentation, which is still available to view on our website, we gave updates and had external KOLs, talk about some existing clinical programs in cardiometabolic and pulmonary disease and discuss what's next for us in CNS tissue, including potentially systemic delivery and delivery to adipose tissue. The R&D Day had a lot of detail. We are constantly pushing our technology forward and expanding its reach.

最後，在將一切交給哈維爾之前，我想強調一下我們在 6 月份舉辦的研發日。在該演示文稿中（仍然可以在我們的網站上查看），我們提供了最新信息並邀請了外部KOL，討論了心臟代謝和肺部疾病方面的一些現有臨床項目，並討論了我們在中樞神經系統組織中的下一步發展，包括潛在的全身遞送和遞送到脂肪組織。研發日有很多細節。我們不斷推動我們的技術向前發展並擴大其影響範圍。

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. The design, planning and preparation of the late-stage studies of our cardiometabolic candidates, ARO-APOC3 and ARO-ANG3 is well underway, while making good progress towards our goal of conducting multiple and a Phase 2 meeting with regulators this year and initiated multiple Phase 3 studies late this year and early next year.

謝謝克里斯，大家下午好。我們的心臟代謝候選藥物ARO-APOC3 和ARO-ANG3 的後期研究的設計、規劃和準備工作正在順利進行，同時在實現今年與監管機構舉行多次會議和第二階段會議並發起多項會議的目標方面取得了良好進展。第三階段研究將於今年年底和明年初進行。

We also intend to present final Phase 2 data at the American Higher Association meeting in November, pending acceptance for multiple studies for both ARO-APOC3 and ARO-ANG3.

我們還打算在 11 月的美國高等教育協會會議上公佈最終的第 2 階段數據，等待 ARO-APOC3 和 ARO-ANG3 多項研究的接受。

Let's take a moment to review the various studies we have conducted, and then I will provide our current thinking around the Phase 3 studies, may -- how the Phase 3 study may look like for each clinical indication.

讓我們花點時間回顧一下我們已經進行的各種研究，然後我將提供我們目前圍繞 3 期研究的想法——3 期研究對於每種臨床適應症可能會是什麼樣子。

I will start with ARO-APOC3. Our investigational RNAi therapeutic being developed as a treatment for patients with mixed dyslipidemia, severe hypertriglyceridemia and familial chylomicronemia syndrome. ARO-APOC3 is designed to reduce production of apolipoprotein C-III, or APOC3, a component of triglyceride rich lipoproteins, including very low-density lipoproteins, or VLDL and chylomicrons and is a key regulator of triglycerides metabolism. Knocking down the hepatic production of APOC3 by RNAi results in reduced VLDL synthesis and assembly, enhanced breakdown of triglyceride-rich lipoproteins, and better clearance of VLDL and chylomicron remnants via LDL dependent and independent pathways.

我將從 ARO-APOC3 開始。我們的研究性 RNAi 療法正在開髮用於治療混合性血脂異常、嚴重高甘油三酯血症和家族性乳糜微粒血症綜合徵患者。 ARO-APOC3 旨在減少載脂蛋白C-III 或APOC3 的產生，載脂蛋白C-III 是富含甘油三酯的脂蛋白的組成部分，包括極低密度脂蛋白或VLDL 和乳糜微粒，是甘油三酯代謝的關鍵調節劑。通過 RNAi 減少肝臟產生 APOC3 會導致 VLDL 合成和組裝減少，富含甘油三酯的脂蛋白的分解增強，並通過 LDL 依賴性和獨立途徑更好地清除 VLDL 和乳糜微粒殘留物。

We view ARO-APOC3 as having the potential to address many patients population with various lipid disorders that can lead to different clinical complications and FeNO types. Familial Chylomicronemia Syndrome, or FCS is characterized by extremely high TG levels typically over 1,000 milligrams per deciliter and as high as 5,000 milligrams per deciliter, leading the high rates of acute pancreatitis that usually requires hospitalization and can be fatal.

我們認為 ARO-APOC3 有潛力解決許多患有各種脂質疾病的患者群體，這些疾病可能導致不同的臨床並發症和 FeNO 類型。家族性乳糜微粒血症綜合徵(FCS) 的特點是TG 水平極高，通常超過1,000 毫克/分升，最高可達5,000 毫克/分升，導致急性胰腺炎發病率很高，通常需要住院治療，並且可能致命。

Patients with FCS may also experience chronic abdominal pain, and they have to adhere to a very strict diet with very low fat content, leading to impair their quality of life. FCS is a severe and ultra rare genetic disease that affects hundreds to a few thousand patients in the U.S.

FCS患者還可能經歷慢性腹痛，他們必須堅持非常嚴格的低脂肪飲食，導致生活質量受到損害。 FCS 是一種嚴重且極其罕見的遺傳病，影響美國數百至數千名患者。

Severe hypertriglyceridemia, or SHTG is characterized by marked elevation in TG levels, typically over 500 milligrams per deciliter, which can lead to increased risk of acute pancreatitis, as well as an increased risk of cardiovascular disease. This condition is estimated to affect several million patients in the U.S.

嚴重高甘油三酯血症（SHTG）的特點是 TG 水平顯著升高，通常超過 500 毫克/分升，這可能導致急性胰腺炎的風險增加，以及心血管疾病的風險增加。據估計，這種情況會影響美國數百萬患者。

Lastly, mixed dyslipidemia is defined as the presence of high LDL cholesterol combined with TGs remnant cholesterol and low HDL. The lipid profile is a major component of the risk factor for atherosclerosis cardiovascular. There are likely tens of millions of patients in the U.S. with mixed dyslipidemia who are not adequately control with current standard of care.

最後，混合性血脂異常被定義為同時存在高 LDL 膽固醇、TG 殘餘膽固醇和低 HDL。血脂是動脈粥樣硬化心血管危險因素的主要組成部分。在美國，可能有數千萬患有混合性血脂異常的患者，他們目前的護理標準無法得到充分控制。

The studies of ARO-APOC3 that we have conducted or are planning to conduct for each population are as follows. For FCS, we are conducting the PALISADE study, which is a Phase 3 placebo-controlled study to evaluate the efficacy and safety of ARO-APOC3 in adults with FCS. The primary endpoint for this study is percent change from baseline in fasting TG at month 10. This study was fully enclosed in May with a total of 75 subjects distributed across 39 different sites in 18 countries who were randomized to receive 25 milligrams of ARO-APOC3, 50 milligrams of ARO-APOC3, or matching placebo once every 3 months.

我們已經對每個人群進行或計劃進行的ARO-APOC3研究如下。對於 FCS，我們正在進行 PALISADE 研究，這是一項 3 期安慰劑對照研究，旨在評估 ARO-APOC3 在成人 FCS 中的有效性和安全性。這項研究的主要終點是第10 個月空腹TG 相對於基線的變化百分比。這項研究於5 月份完全封閉，共有75 名受試者分佈在18 個國家的39 個不同地點，他們被隨機接受25 毫克ARO-APOC3 、 50 毫克 ARO-APOC3，或每 3 個月一次匹配的安慰劑。

This puts us on schedule for study completion in Q2 of 2024, a data readout shortly thereafter, and then NDA preparation for regulatory filings. Participants who completed randomized portion of PALISADE are also eligible to continue in an extension period, where all participants will receive ARO-APOC3.

這使我們按計劃在 2024 年第二季度完成研究，隨後不久就會讀出數據，然後為監管備案準備新藥申請 (NDA)。完成 PALISADE 隨機部分的參與者也有資格繼續延長期限，所有參與者都將收到 ARO-APOC3。

For SHTG, we are conducting the SHASTA-2 Phase 2 study in 229 patients randomized 3:1 to receive 10, 25 or 50 milligrams of ARO-APOC3, all placebo on day 1 and week 12. Patients with FCS were excluded from this study. The primary endpoint is percent change from baseline fasting TG at week 24. SHASTA-2 was the study that enabled us to begin planning and design for our Phase 3 plan in SHTG patients. The data strongly support advancement into Phase 3, and we plan to present results at the American Heart Association in November. The current Phase 3 plan for SHTG includes 2 separate studies, which will be called SHASTA-3 and SHASTA-4. The idea behind the 2 studies is to have, first, a faster path to regulatory submission with the SHASTA-3 study, a double-blind, 12-month randomized control study of approximately 600 patients with TGs greater than 500 million per deciliter.

對於SHTG，我們正在對229 名患者進行SHASTA-2 2 期研究，這些患者按照3:1 的比例隨機接受10、25 或50 毫克ARO-APOC3，在第1 天和第12 週均為安慰劑。 FCS 患者被排除在本研究之外。主要終點是第 24 週時相對於基線空腹 TG 的變化百分比。SHASTA-2 是一項研究，使我們能夠開始規劃和設計針對 SHTG 患者的 3 期計劃。這些數據強烈支持進入第三階段，我們計劃於 11 月在美國心臟協會公佈結果。 SHTG 目前的第 3 階段計劃包括兩項獨立的研究，分別稱為 SHASTA-3 和 SHASTA-4。這兩項研究背後的想法是，首先，通過SHASTA-3 研究，可以更快地向監管機構提交申請。SHASTA-3 研究是一項雙盲、為期12 個月的隨機對照研究，受試者為約600 名TG 大於5 億每分升的患者。

We believe this study plus the large safety database from our Phase 1 and 2 study will be an appropriate package for an initial filing the SHTG indication. The second study, SHTG-4 is decided to investigate the effect of ARO-APOC3 in a more severe population at high risk of developing pancreatitis.

我們相信這項研究加上我們 1 期和 2 期研究的大型安全數據庫將成為初次提交 SHTG 適應症的合適方案。第二項研究 SHTG-4 決定調查 ARO-APOC3 對患有胰腺炎高風險的更嚴重人群的影響。

SHASTA-4 will include patients with TG greater than 880 milligrams per deciliter and recent history of pancreatitis. The duration of the double-blind portion of the study will be 2 years, and it will be powered to detect difference in the incidence of pancreatitis. This data could enable label expansion to include the indication statement of pancreatitis risk reduction, a key clinical outcome relevant to patients and reimbursement authorities.

SHASTA-4 將包括 TG 大於 880 毫克/分升且近期有胰腺炎病史的患者。該研究的雙盲部分持續時間為2年，旨在檢測胰腺炎發病率的差異。這些數據可以使標籤擴展包括減少胰腺炎風險的適應症聲明，這是與患者和報銷機構相關的關鍵臨床結果。

We have made a lot of progress on the planning and design of these studies and intend to have discussion with regulators this year and move forward rapidly with studies initiation. We will provide more details on the study when they begin.

我們在這些研究的規劃和設計方面已經取得了很多進展，並打算今年與監管機構進行討論，並迅速推進研究的啟動。我們將在研究開始時提供有關該研究的更多詳細信息。

In the broader mixed dyslipidemia population, we're conducting the new Phase 2 study in 653 patients randomized 3:1 to receive 10, 25, or 50 milligrams of ARO-APOC3 or placebo on day 1 and at week 12. We included an additional cohort of participants receiving 50 milligrams on day 1 and week 24. The primary endpoint is prevention from baseline in fasting TG at week 24, with additional assessment of the changes in various lipid parameters such as LDL cholesterol, non-HDL-C, HDL, ApoA-V, and VLDL, and other biomarkers.

在更廣泛的混合性血脂異常人群中，我們正在對653 名患者進行新的2 期研究，這些患者按照3:1 的比例隨機分配，在第1 天和第12 週接受10、25 或50 毫克ARO-APOC3 或安慰劑。參與者隊列在第1 天和第24 週接受50 毫克。主要終點是在第24 週時預防空腹TG 偏離基線，並額外評估各種脂質參數的變化，例如LDL 膽固醇、非HDL-C、HDL、 ApoA-V、VLDL 和其他生物標誌物。

Similar to the SHTG study results, we believe the Phase 2 data from the newer studies strongly support advancement into a Phase 3 study, and we also plan to present these results at the American Heart. The Phase 3 program for this population will be a cardiovascular outcome trial called CASCADE. ARO-APOC3 has demonstrated positive effect on several lipid parameters that represent residual risk factors for arteriosclerosis cardiovascular disease even after LDL is well controlled.

與 SHTG 研究結果類似，我們相信新研究的 2 期數據強烈支持進入 3 期研究，我們還計劃在美國心臟中心展示這些結果。針對這一人群的第三階段計劃將是一項名為 CASCADE 的心血管結果試驗。即使在 LDL 得到良好控制後，ARO-APOC3 對代表動脈硬化性心血管疾病殘留危險因素的幾個脂質參數也表現出積極作用。

The CASCADE study will select the patient population with high risk driven by the high TGs, remnant cholesterol, and low HDL, all of which are effectively addressed by ARO-APOC3.

CASCADE研究將選擇由高TG、殘餘膽固醇和低HDL驅動的高風險患者人群，所有這些都可以通過ARO-APOC3有效解決。

The study will be designed in collaboration with an Academic Research Organization, or ARO, we’re working on all aspects of the study design, including selection of the patient population, understanding and modeling background events rates, the potential effect size, and with that information we'll define the sample size and duration of exposure to be able to detect a clinically meaningful reduction in cardiovascular events.

該研究將與學術研究組織 (ARO) 合作設計，我們正在研究研究設計的各個方面，包括患者群體的選擇、背景事件發生率的理解和建模、潛在的效應大小，並利用這些信息，我們將定義樣本大小和暴露持續時間，以便能夠檢測出具有臨床意義的心血管事件減少。

We’re finalizing agreement with the selected CRO and ARO to help us conduct this important study. We are scheduled to engage with regulators later this year and plan to initiate the CASCADE study in 2024. Our strategy for ARO-APOC3 is to progressively study in larger and longer studies to potentially bring it to very high prevalence disease population that currently do not have adequate treatment options.

我們正在與選定的 CRO 和 ARO 敲定協議，以幫助我們開展這項重要的研究。我們計劃在今年晚些時候與監管機構合作，併計劃在2024 年啟動CASCADE 研究。我們對ARO-APOC3 的策略是逐步進行規模更大、時間更長的研究，以有可能將其應用於目前尚未發現的患病率非常高的人群。足夠的治療選擇。

Our strategy for ARO-ANG3 is more focused on smaller well-defined population, ARO-ANG3 is being developed as a treatment for homozygous familial hypercholesterolemia or HoFH, and potentially in the future success of heterozygous familial hypercholesterolemia, or HeFH.

我們的ARO-ANG3 策略更側重於較小的明確人群，ARO-ANG3 正在開髮用於治療純合子家族性高膽固醇血症(HoFH)，並有可能在未來成功治療雜合子家族性高膽固醇血症(HeFH)。

Phase 2 program for ARO-ANG3 involved 2 studies, the ARCHES-2 Phase 2 study in 204 patients with mixed dyslipidemia and the GATEWAY study in 18 patients with HoFH. Interim data from the GATEWAY study was presented at the 91st European Atherosclerosis Society Congress in May of 2023.

ARO-ANG3 的 2 期計劃涉及 2 項研究，即針對 204 名混合性血脂異常患者的 ARCHES-2 2 期研究和針對 18 名 HoFH 患者的 GATEWAY 研究。 GATEWAY 研究的中期數據已在 2023 年 5 月舉行的第 91 屆歐洲動脈粥樣硬化學會大會上公佈。

At study week 20, administration of 200 milligrams, or 300 milligrams ARO-ANG3 on day 1 and day 8, 4 led to mean reductions in LDL cholesterol of 48.1% and 44%, respectively. These reductions were achieved on top of continuous standard of care, including statins, ezetimibe, PCSK9 inhibitors, and apheresis.

在研究第 20 週，在第 1 天和第 8、4 天施用 200 毫克或 300 毫克 ARO-ANG3 分別導致 LDL 膽固醇平均降低 48.1% 和 44%。這些減少是在持續標準​​護理的基礎上實現的，包括他汀類藥物、依折麥布、PCSK9 抑製劑和血漿分離術。

These results were on par with an approval monoclonal antibody that also target ANGPTL3, ARO-ANG3 has a much more convenient and patient-friendly dosing regimen of one subcutaneous injection every 3 months versus the antibody, which requires an intravenous infusion once a month. We're currently working on the Phase 3 study design and plan for ARO-ANG3 in HoFH and assessing potential other population for future studies.

這些結果與已批准的同樣靶向 ANGPTL3 的單克隆抗體相當，ARO-ANG3 的給藥方案更方便、更適合患者，每 3 個月皮下注射一次，而抗體則需要每月靜脈注射一次。我們目前正在 HoFH 中進行 ARO-ANG3 的 3 期研究設計和計劃，並評估未來研究的潛在其他人群。

I spoke in a bit more detail on both ARO-APOC3 and ARO-ANG3 during our R&D day in June. I recommend you view the archived webcast, or presentation slides on our website, if you want more background on the biology of the target, some of the clinical data, the rationale for our belief in their potential and more specific information about our plans for clinical development.

我在 6 月份的研發日期間更詳細地介紹了 ARO-APOC3 和 ARO-ANG3。如果您想了解有關目標生物學的更多背景信息、一些臨床數據、我們相信其潛力的理由以及有關我們臨床計劃的更多具體信息，我建議您查看我們網站上的存檔網絡廣播或演示幻燈片發展。

The other late-stage program we're working on with our partner, Takeda, is fazirsiran for the treatment of AATD liver disease. In June, update the Phase 2 clinical data from the SEQUOIA study were presented at EASL Congress 2023 in an oral presentation. The clinical results from the Phase 2 SEQUOIA study of fazirsiran were clear and compelling. Fazirsiran treatment demonstrated substantial effect on several key marker of liver disease.

我們與合作夥伴武田 (Takeda) 合作的另一個後期項目是用於治療 AATD 肝病的 fazirsiran。 6 月，更新了 SEQUOIA 研究的 2 期臨床數據，並在 2023 年 EASL 大會上進行了口頭報告。 fazirsiran 的 2 期 SEQUOIA 研究的臨床結果是明確且令人信服的。 Fazirsiran 治療對肝病的幾個關鍵標誌物具有顯著效果。

Takeda has taken the lead in conducting the e Phase 3 REDWOOD clinical study. It is designed to enroll 160 adult patients with F2 to F4 fibrosis. The primary endpoint of the study is to decrease from baseline of at least 1 stage at week 106 in patients with F2 and F3 fibrosis.

武田已牽頭開展 e 3 期 REDWOOD 臨床研究。它旨在招募 160 名 F2 至 F4 纖維化成年患者。該研究的主要終點是 F2 和 F3 纖維化患者在第 106 週時從基線減少至少 1 個階段。

Takeda is doing an outstanding job at bringing global sites online for the REDWOOD study and enrolling patients efficiency. Additional information on the REDWOOD study can be found at theredwoodliverstudy.com.

武田在將 REDWOOD 研究的全球網站上線並提高患者入組效率方面做得非常出色。有關 REDWOOD 研究的更多信息，請訪問 theredwoodliverstudy.com。

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

我現在將電話轉給詹姆斯·漢密爾頓博士，詹姆斯？

Thank you, Javier. Our pipeline of early-stage clinical candidates now includes 8 programs addressing various diseases with gene expression in 4 tissue types, including liver, lung and now muscle and CNS.

謝謝你，哈維爾。我們的早期臨床候選產品管道現在包括 8 個項目，針對 4 種組織類型中基因表達的各種疾病，包括肝臟、肺臟以及現在的肌肉和中樞神經系統。

Of these 8 programs, most are wholly-owned and in our core areas of focus; they are in pulmonary, ARO-RAGE, ARO-MUC5AC, ARO-MMP7, in cardiometabolic ARO-PNPLA3, in neuromuscular ARO-DUX4 and ARO-SOD1, and we also have ARO-C3 for complement-mediated diseases and HZN-457 partnered with Horizon for Gout.

在這 8 個項目中，大多數是全資擁有的，並且屬於我們的核心關注領域；它們在肺部、ARO-RAGE、ARO-MUC5AC、ARO-MMP7、心臟代謝ARO-PNPLA3、神經肌肉ARO-DUX4 和ARO-SOD1 中，我們還有用於補體介導疾病的ARO-C3 和HZN-457合作與地平線治療痛風。

In addition, we have many undisclosed preclinical programs that should continue to feed our pipeline for years to come. We are increasingly looking for opportunities to focus around core areas, and we are fortunate that our platform provides us with so many opportunities.

此外，我們還有許多未公開的臨床前項目，這些項目應該會在未來幾年繼續為我們的產品線提供支持。我們越來越多地尋找機會專注於核心領域，我們很幸運我們的平台為我們提供瞭如此多的機會。

Our discovery and clinical development teams continue to be highly productive and efficient. One main benefit of drug development based on a proprietary technology platform is that it allows us to apply learnings from prior programs to each new program. This makes us faster, more precise, and I believe, yields drug candidates with a higher probability of success.

我們的發現和臨床開發團隊繼續保持高生產力和高效率。基於專有技術平台的藥物開發的一個主要好處是，它使我們能夠將先前項目的經驗應用到每個新項目中。這使我們更快、更精確，而且我相信，我們能夠生產出成功概率更高的候選藥物。

The TRiM platform has given us that advantage for liver-directed programs for a few years now. We believe we are now in a period where those same advantages exist for lung-directed programs and we have the potential to get there over the next couple of years for muscle and CNS.

幾年來，TRiM 平台為我們提供了肝臟導向項目的優勢。我們相信，我們現在正處於一個針對肺部的項目也存在同樣優勢的時期，並且我們有潛力在未來幾年內為肌肉和中樞神經系統實現這一目標。

We held a very comprehensive R&D Day during the quarter, so I'm not going to review all of Arrowhead's discovery and early development programs. I'd like to focus on some important potentially derisking data from our ARO-RAGE program.

我們在本季度舉辦了一次非常全面的研發日，因此我不會回顧 Arrowhead 的所有發現和早期開發計劃。我想重點關注來自我們 ARO-RAGE 計劃的一些重要的潛在風險數據。

ARO-RAGE is our RNAi therapeutic candidate designed to reduce expression of the receptor for advanced glycation end products, or RAGE, as a potential treatment for inflammatory pulmonary diseases such as asthma.

ARO-RAGE 是我們的 RNAi 治療候選藥物，旨在減少晚期糖基化終末產物（RAGE）受體的表達，作為哮喘等炎症性肺部疾病的潛在治療方法。

We are currently conducting a Phase 1/2a clinical trial in normal healthy volunteers and in patients with mild to moderate asthma. We have also recently filed an amendment to add 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.

我們目前正在正常健康志願者和輕度至中度哮喘患者中進行 1/2a 期臨床試驗。我們最近還提交了一項修正案，添加了一組呼出一氧化氮（FeNO）基線水平較高的哮喘患者，FeNO 是肺部 IL-13 驅動的 2 型炎症程度的生物標誌物。

Let's talk briefly about what data we generated and reported at the R&D Day. First, with respect to safety and tolerability, to-date, there have been no reported serious or severe adverse events, no study withdraws or drug discontinuations due to adverse events, and safety labs have shown no pattern of adverse changes. There have also been no change -- have also been no change in the pattern of airway immune cells and all chest x-rays have been read as normal. These encouraging results have also been generally consistent in the ARO-MMP7 and ARO-MUC5AC programs.

讓我們簡單談談我們在研發日生成和報告了哪些數據。首先，在安全性和耐受性方面，迄今為止，還沒有報告嚴重或嚴重的不良事件，沒有因不良事件而撤回或停止藥物的研究，安全實驗室也沒有顯示出不良變化的模式。氣道免疫細胞的模式也沒有變化，所有胸部 X 光檢查都顯示為正常。這些令人鼓舞的結果在 ARO-MMP7 和 ARO-MUC5AC 項目中也基本一致。

With respect to activity, the results to-date, especially, at the highest dose level, have exceeded our estimates and really represent a best case scenario for target engagement. We are measuring soluble RAGE protein or sRAGE, in serum after multiple doses in both healthy volunteers and in patients and in BALF after a single dose in healthy volunteers and after multi doses -- multiple doses at the top dose level.

就活動而言，迄今為止的結果，特別是在最高劑量水平下，已經超出了我們的估計，並且真正代表了目標參與的最佳情況。我們正在測量健康志願者和患者多劑量後血清中的可溶性 RAGE 蛋白或 sRAGE，以及健康志願者單劑量和多劑量（最高劑量水平的多劑量）後 BALF 中的可溶性 RAGE 蛋白或 sRAGE。

The mean maximum reduction in sRAGE at the 92 milligram dose level after 2 doses on days 1 and 29 was 80% with a maximum reduction of 90%, with a long duration of effect that supports every other month dosing. At the highest dose of 184 milligrams, we achieved a similar result after just a single dose, with mean sRAGE reduction of up to 76% and maximal reduction of 91%.

在第 1 天和第 29 天注射 2 劑後，92 毫克劑量水平的 sRAGE 平均最大減少量為 80%，最大減少量為 90%，作用持續時間長，支持每隔一個月給藥一次。在最高劑量 184 毫克時，我們僅在單次劑量後就獲得了類似的結果，平均 sRAGE 降低高達 76%，最大降低 91%。

We also observed a continued dose response in BALF with a single inhaled dose of 184 milligrams, achieving mean reduction up 90% and maximal reduction of 95%. We are still collecting data that we intend to report on later this year, including presentations at the European Respiratory Society International Congress in September.

我們還觀察到單次吸入 184 毫克劑量在 BALF 中的持續劑量反應，實現平均減少 90% 和最大減少 95%。我們仍在收集打算在今年晚些時候報告的數據，包括在 9 月份的歐洲呼吸學會國際大會上的演講。

We believe this is the first compelling clinical evidence of gene target silencing in the lung using sRNA. We also believe that these clinical results have a good chance of being predictive of clinical results in other pulmonary programs, including ARO-MUC5AC and ARO-MMP7 and additional undisclosed preclinical programs.

我們相信這是使用 sRNA 在肺部進行基因靶標沉默的第一個令人信服的臨床證據。我們還相信，這些臨床結果很有可能預測其他肺部項目的臨床結果，包括 ARO-MUC5AC 和 ARO-MMP7 以及其他未公開的臨床前項目。

And lastly, on RAGE, what data are we generating over the coming months? We will have the chronic monkey GLP toxicology results before the end of the year, which will be needed prior to Phase 2 initiation. We will be getting additional longer-term follow-up and multiple dose data at the highest doses in healthy volunteers and in patients later this year and into next year.

最後，在 RAGE 上，我們在未來幾個月會生成哪些數據？我們將在今年年底之前獲得慢性猴 GLP 毒理學結果，這是第二階段啟動之前所需要的。我們將在今年晚些時候和明年獲得健康志願者和患者的額外長期隨訪和最高劑量的多劑量數據。

Lastly, we will be getting data from the high FeNO cohorts, which is designed to assess if RAGE knockdown leads to an IL-13 specific anti-inflammatory effect. This study is not long enough or large enough to expect an efficacy signal, but signals of inflammatory pathway inhibition after short course of exposure would be a welcome result. We expect these data in 2024.

最後，我們將從高 FeNO 隊列中獲取數據，該數據旨在評估 RAGE 敲低是否會導致 IL-13 特異性抗炎作用。這項研究的時間和規模還不夠長，不足以期待療效信號，但短期暴露後炎症途徑抑制的信號將是一個受歡迎的結果。我們預計這些數據將在 2024 年公佈。

I also want to provide an update on our earliest clinical candidates. During the last quarter, we filed CTAs for our first muscle and CNS candidates, ARO-DUX4 and ARO-SOD1, respectively. ARO-DUX4 is the first clinical candidate utilizing the TRiM platform to target disease-associated genes in skeletal muscle. ARO-DUX4 is an investigational RNAi therapeutic designed to reduce expression of the gene that encodes the human double homeobox 4 or DUX4 protein as a potential treatment for facioscapulohumeral muscular dystrophy, or FSHD.

我還想提供有關我們最早的臨床候選人的最新信息。在上個季度，我們分別為我們的第一個肌肉和 CNS 候選藥物 ARO-DUX4 和 ARO-SOD1 提交了 CTA。 ARO-DUX4 是第一個利用 TRiM 平台靶向骨骼肌中疾病相關基因的臨床候選藥物。 ARO-DUX4 是一種研究性 RNAi 療法，旨在減少編碼人類雙同源盒 4 或 DUX4 蛋白的基因表達，作為面肩肱型肌營養不良症 (FSHD) 的潛在治療方法。

Pending regulatory clearance, we intend to proceed with a Phase 1/2a dose-escalating study to evaluate ARO-DUX4 in adult patients with FSHD type 1. The study is designed to enroll up to 52 patients.

在等待監管機構批准之前，我們打算進行一項 1/2a 期劑量遞增研究，以評估 ARO-DUX4 在 1 型 FSHD 成年患者中的作用。該研究旨在招募最多 52 名患者。

The other CTA filed during the quarter was for ARO-SOD1, the first therapeutic candidate designed for delivery to the CNS, again, leveraging the TRiM platform. ARO-SOD1 is designed to reduce expression of superoxide dismutase 1, or SOD1 in CNS as a potential treatment for patients with amyotrophic lateral sclerosis, or ALS caused by SOD1 mutations.

本季度提交的另一項 CTA 是針對 ARO-SOD1，這是第一個設計用於輸送至中樞神經系統的候選治療藥物，同樣利用 TRiM 平台。 ARO-SOD1 旨在減少中樞神經系統中超氧化物歧化酶 1 或 SOD1 的表達，作為治療由 SOD1 突變引起的肌萎縮側索硬化症或 ALS 患者的潛在治療方法。

Pending regulatory clearance, we intend to proceed with a Phase 1 dose escalating study to evaluate ARO-SOD1 in adult patients with ALS harboring a SOD1 mutation, which is considered to be causative of ALS. The study is designed to enroll up to 24 patients.

在等待監管部門批准之前，我們打算進行一項 1 期劑量遞增研究，以評估 ARO-SOD1 在患有 SOD1 突變的成年 ALS 患者中的作用，SOD1 突變被認為是 ALS 的病因。該研究計劃招募多達 24 名患者。

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 the quarter ended June 30, 2023, was $102.9 million, or $0.96 per share based on 107 million fully diluted weighted average shares outstanding. This compares with a net loss of $72 million, or $0.68 per share based on 105.8 million fully diluted weighted average shares outstanding for the quarter ended June 30, 2022.

謝謝詹姆斯，大家下午好。正如我們今天報告的那樣，截至 2023 年 6 月 30 日的季度淨虧損為 1.029 億美元，即根據 1.07 億股完全稀釋加權平均流通股計算，每股虧損 0.96 美元。相比之下，淨虧損為 7200 萬美元，即每股虧損 0.68 美元（基於截至 2022 年 6 月 30 日的季度的 1.058 億股完全稀釋加權平均流通股計算）。

Revenue for the quarter ended June 30, 2023, was $15.8 million, compared to $32.4 million for the quarter ended June 30, 2022. Revenue in the current period primarily relates to our collaboration agreement with Takeda. Revenue is recognized as we complete our performance obligations, which include managing the ongoing AAT Phase 2 clinical trials for Takeda. There remains $17 million of revenue to be recognized associated with the Takeda collaboration, which we anticipate will be recognized over the next year.

截至 2023 年 6 月 30 日的季度收入為 1,580 萬美元，而截至 2022 年 6 月 30 日的季度收入為 3,240 萬美元。本期收入主要與我們與武田的合作協議有關。當我們完成履約義務時確認收入，其中包括管理武田正在進行的 AAT 二期臨床試驗。與武田合作相關的收入仍有 1700 萬美元需要確認，我們預計將在明年確認。

Total operating expenses for the quarter ended June 30, 2023, were $118.5 million compared with $105.3 million for the quarter ended June 30, 2022. The key drivers of this change were increased candidate costs, partially offset by lower stock compensation expense. The increased candidate costs were primarily due to the progression of the company's pipeline of candidates into the -- into and through clinical trials, which resulted in higher outsourced clinical trial, toxicity study and manufacturing costs.

截至2023 年6 月30 日的季度的總運營費用為1.185 億美元，而截至2022 年6 月30 日的季度的總運營費用為1.053 億美元。這一變化的主要驅動因素是候選人成本增加，但部分被較低的股票薪酬費用所抵消。候選藥物成本增加主要是由於該公司的候選藥物管道進入臨床試驗並通過臨床試驗，這導致外包臨床試驗、毒性研究和製造成本增加。

Net cash used in operating activities during the 3 months ended June 30, 2023, was $21.4 million, compared with net cash used in operating activities of $68.9 million for the 3 months ended June 30, 2022. We expect our operating cash burn to be $80 million to $90 million next quarter. We expect to spend between $160 million and $180 million over the next 3 quarters to complete our GMP manufacturing facility and related laboratories in Verona, Wisconsin.

截至2023年6月30日的三個月經營活動使用的現金淨額為2140萬美元，而截至2022年6月30日的三個月經營活動使用的現金淨額為6890萬美元。我們預計我們的經營現金消耗為80美元下一季度 100 萬至 9000 萬美元。我們預計在未來 3 個季度花費 1.6 億至 1.8 億美元來完成我們位於威斯康星州維羅納的 GMP 生產設施和相關實驗室。

Turning to our balance sheet. Our cash and investments totaled $494.5 million at June 30, 2023, compared to $482.3 million at September 30, 2022. The increase in our cash and investments was primarily related to the $250 million payment from the royalty -- from Royalty Pharma as well as other licensing cash inflows offset by our operating cash burn, along with continuing capital projects. Our common shares outstanding at June 30, 2023, were 107.1 million.

轉向我們的資產負債表。截至2023 年6 月30 日，我們的現金和投資總額為4.945 億美元，而截至2022 年9 月30 日為4.823 億美元。我們的現金和投資增加主要與特許權使用費支付的2.5 億美元有關——來自Royalty Pharma 以及其他公司許可現金流入被我們的運營現金消耗以及持續的資本項目所抵消。截至 2023 年 6 月 30 日，我們的已發行普通股為 1.071 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. We are well on our way to reaching our 2025 goal to grow our pipeline of RNAi therapeutics to a total of 20 clinical stage, or marketed product from the year 2025. However, pipeline expansion is just a means to an end. The ultimate goal and the reason we continue to invest in expanding our platform, discovering new candidates, advancing our clinical programs, and streamlining the drug manufacturing process is that it allows us to get important new medicines to patients in need as quickly and efficiently as possible.

謝謝，肯。我們正在順利實現 2025 年的目標，即從 2025 年起將我們的 RNAi 療法產品線擴大到總共 20 個臨床階段，或上市產品。然而，管道擴張只是達到目的的一種手段。我們繼續投資擴大平台、發現新候選藥物、推進臨床項目和簡化藥物生產流程的最終目標和原因是，它使我們能夠盡快、高效地為有需要的患者提供重要的新藥。

Doing this will also create a sustainable business and provide a steady stream of commercial revenue, which we now have a better line of sight on and a plan that we are executing to get there.

這樣做還將創造一個可持續的業務並提供穩定的商業收入流，我們現在對此有了更好的視野，並且我們正在執行一個計劃來實現這一目標。

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

感謝您今天加入我們，現在我想開始回答您的問題。操作員？

Our first question comes from Luca Issi of RBC Capital.

我們的第一個問題來自 RBC Capital 的 Luca Issi。

Just a quick one here. I'm wondering if you can comment on what was your reaction to the Roche and Alnylam's deal. I guess 2 questions there. Is AGT a target that you may be willing to pursue? And 2, how should we think about read-through for your cardiovascular franchise?

這裡只是快速介紹一下。我想知道您是否可以評論一下您對羅氏和 Alnylam 交易的反應。我想有兩個問題。 AGT 是您願意追求的目標嗎？ 2，我們應該如何考慮心血管專營權的通讀？

And then maybe a super quick one for Javier for severe hypertriglyceridemia. I was under the impression that you were planning a single pivotal trial with triglycerides as a primary endpoint and pancreatitis as a secondary point. However, it sounds today like you're planning 2 separate studies, so I'm wondering what drove that change?

然後，對於哈維爾來說，可能是治療嚴重高甘油三酯血症的超級快速療法。我的印像是，您正在計劃一項以甘油三酯為主要終點、胰腺炎為次要終點的單一關鍵試驗。然而，今天聽起來您正在計劃兩項單獨的研究，所以我想知道是什麼推動了這一變化？

Sure. So, I don't know that we have really a position on the Alnylam-Roche deal, good for them. We are not working on that target. It didn't fit into where we see opportunities in the space. And I don't think it reads through to our cardiometabolic assets. I think those are really orthogonal to each other. Javier, do you want to address?

當然。所以，我不知道我們在 Alnylam-Roche 交易中是否真的持有立場，這對他們有利。我們並沒有為這個目標而努力。它不符合我們在該領域看到的機會。我不認為它能解讀我們的心臟代謝資產。我認為這些確實是相互正交的。哈維爾，你想講話嗎？

Yes. I think when we presented the clinical program for ARO-APOC3 at the R&D Day, I think I mentioned that we are doing 2 studies. The first one, which is the one that would be the primary source of registration is the SHASTA-3, which is 600 patients approximately with TG higher than 500.

是的。我想當我們在研發日展示 ARO-APOC3 的臨床計劃時，我想我提到過我們正在做兩項研究。第一個是 SHASTA-3，也是註冊的主要來源，其中大約有 600 名 TG 高於 500 的患者。

But we will start in parallel the study SHASTA-4 in patients with higher TG levels and recent past history of pancreatitis. That study would be approximately 200 patients, and that will not be part of the initial filing, but it will be a subsequent interaction with the agency, hopefully, to get pancreatitis risk reduction in that study and eventually add that to the label. So, it was planned, but there is a sequence here. First, SHASTA-3 registration and second SHASTA-4 label expansion.

但我們將同時在 TG 水平較高且近期有胰腺炎病史的患者中開始 SHASTA-4 研究。該研究將涉及大約 200 名患者，這不會成為最初申請的一部分，但將是隨後與該機構的互動，希望能夠降低該研究中的胰腺炎風險，並最終將其添加到標籤中。所以，這是計劃好的，但這裡有一個順序。首先，SHASTA-3 註冊和第二次 SHASTA-4 標籤擴展。

Our next question comes from Maury Raycroft of Jefferies.

我們的下一個問題來自 Jefferies 的 Maury Raycroft。

For your pulmonary platform, you've got the late-breaker title for your RAGE program at ERS next month. How much asthma patient data can we expect in this update? Or will it be longer-term follow-up from this SAD and MAD healthy volunteer part of the study?

對於您的肺部平台，您已獲得下個月在 ERS ​​舉行的 RAGE 項目的最新冠軍頭銜。此次更新中我們可以期待多少哮喘患者數據？還是該研究的 SAD 和 MAD 健康志願者部分的長期隨訪？

And then separately, I wanted to clarify for the preclin tox studies, are those 6 months or 12 months? And it sounds like you're somewhat beyond where you were with ENaC on safety, can you just elaborate more on that as it relates to the preclinical and clinical data that you've got so far?

然後，我想分別澄清一下臨床前毒性研究，是 6 個月還是 12 個月？聽起來您在安全性方面似乎超出了 ENaC 的水平，您能否詳細說明一下，因為它與您迄今為止獲得的臨床前和臨床數據有關？

Yes. Sure. I can take the first part of the question. The data that will be presented at European Respiratory is primarily an update on the healthy volunteer SAD and MAD duration. We may have a little bit more duration data from the first patient cohort, the asthmatic patient cohort, but we won't have additional patient data at that time.

是的。當然。我可以回答問題的第一部分。將在歐洲呼吸病學會議上公佈的數據主要是健康志願者 SAD 和 MAD 持續時間的更新。我們可能會從第一個患者隊列（哮喘患者隊列）中獲得更多的持續時間數據，但當時我們不會獲得其他患者數據。

And then regarding the tox studies, the -- this is the 6-month rat tox study that Chris was referring to for both RAGE and MMP7.

然後關於毒性研究，這是 Chris 提到的針對 RAGE 和 MMP7 的為期 6 個月的大鼠毒性研究。

Yes. So, we're still waiting on the 9-month monkey tox and you mentioned that it sounds like we are beyond where we were with ARO-ENaC and I think that is true. We are using substantially less material in all of these candidates in the chronic tox studies, and that appears to be bearing fruit for us.

是的。所以，我們仍在等待 9 個月的猴子毒素，您提到聽起來我們已經超越了 ARO-ENaC 的水平，我認為這是事實。在慢性毒物研究中，我們在所有這些候選藥物中使用的材料大大減少，這似乎為我們帶來了成果。

Our next question comes from Patrick Trucchio of H.C. Wainwright & Company.

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

Just a few follow-up questions. The first one is just around the ARO-RAGE chronic tox data. Can you just clarify, is this data, would it be expected in the third quarter or fourth quarter of calendar 2023? And how would you expect it to differ for that, which was reported from ARO-ENAC, just in terms of how are the doses for these compounds compared to ENAC in these studies specifically?

只是幾個後續問題。第一個是關於 ARO-RAGE 慢性毒性數據。您能否澄清一下，這個數據預計會在 2023 年第三季度還是第四季度出現？您認為 ARO-ENAC 報告的結果與這些研究中這些化合物的劑量與 ENAC 相比有何不同？

And then separately, just also regarding the pulmonary programs in clinical development, there are several, 3 programs in clinical development, at least 1 in preclinical development. Can you give us an idea of what targets you could include for your pulmonary platform as it expands, and to what degree would you be looking at targets with genetic or clinical validation as you look to build out this pulmonary pipeline going forward?

然後分別來說，就臨床開發中的肺部項目而言，有幾個，3個項目在臨床開發中，至少有1個在臨床前開發中。您能否告訴我們，隨著您的肺部平台的擴展，您可以為其納入哪些目標？當您希望未來構建這個肺部管道時，您將在多大程度上考慮基因或臨床驗證的目標？

I'll take the second and James can take the first. I've got the easy one. The answer is, we can't give you too much guidance on undisclosed targets. We are, I get your point, that of course we will be looking at genetically validated targets and clinically validated targets. And that is always our preference. Our -- you've heard us say before, our goal here is to, is to take as little target risk as we can. And one way to do that is to, is to work on the most validated targets that we can. And so we will -- we will certainly be doing that. Will we expand beyond that into -- into some targets that have less validation? Probably. But my hope is that we will - is that in the near to midterm, at least the targets we're focusing on will be well validated. James, you want to address the talks?

我會拿第二個，詹姆斯可以拿第一個。我有一個簡單的。答案是，我們不能給你太多關於未公開目標的指導。我明白你的意思，我們當然會關注基因驗證的目標和臨床驗證的目標。這始終是我們的偏好。您之前曾聽我們說過，我們的目標是盡可能減少目標風險。實現這一目標的一種方法是，盡我們所能，致力於最有效的目標。所以我們會——我們肯定會這樣做。我們是否會擴展到其他一些驗證較少的目標？大概。但我希望，在近期到中期，至少我們關注的目標能夠得到很好的驗證。詹姆斯，你想在會談中發言嗎？

Yes, sure. Patrick, thanks for the question. Regarding talks, so the doses are across the board. Lower for -- for the new pulmonary programs. Lower in terms of exposure. I think most importantly, less frequent. If you recall, we used a, a day, 1, 2, 3, every 2 week dosing regimen for ENAC. And then for our current programs, the -- the dose frequency is spread out much, much less frequent. We're dosing either monthly or every 2 months in the chronic tox studies.

是的，當然。帕特里克，謝謝你的提問。關於會談，劑量是全面的。降低為——新的肺部計劃。曝光度較低。我認為最重要的是，頻率較低。如果您還記得的話，我們對 ENAC 使用了一天、1、2、3 次、每 2 週一次的給藥方案。然後，對於我們當前的計劃，劑量頻率分散得多，頻率要低得多。在慢性毒性研究中，我們每月或每兩個月給藥一次。

And if you look, if you compare the exposure, I want to say it, it, it spans from -- from ENAC being 4x times to ENAC being 20x the amount of material compared to the various newer compounds. We're working on. And that is entirely a testament to -- to how much more potent these follow on compounds are.

如果你看，如果你比較曝光，我想說它，它，它的範圍是——與各種較新的化合物相比，ENAC 是材料量的 4 倍，到 ENAC 是材料量的 20 倍。我們正在努力。這完全證明了這些後續化合物的效力有多強。

Next question is from Keay Nakae of Chardan.

下一個問題來自 Chardan 的 Keay Nakae。

Question about partnering specific -- specifically for the CV assets, you're going to go, go it alone. Initially with some of these Phase 3s, but you do have an outcome study out there planned. If you see success going in alone, does that make it more or less likely that you'll want to partner to do an outcome study?

關於具體合作的問題——特別是對於簡歷資產，你要單獨行動。最初是其中一些第 3 階段，但您確實計劃了一項結果研究。如果您看到獨自取得成功，是否會增加或減少您想要合作進行結果研究的可能性？

So -- so we are, we are planning on doing the -- doing the outcome study for ARO-APOC3 by ourselves. We see that as a very interesting asset and the data have been -- have been very compelling. So we are happy to take that on ourselves. It doesn't mean that we're not going to partner that at some point geographically, potentially. Who knows, but we are happy to take on the CVOT risk ourselves. And so that's our plan right now.

所以，我們正在計劃自己對 ARO-APOC3 進行結果研究。我們認為這是一項非常有趣的資產，而且數據非常引人注目。所以我們很樂意承擔這個責任。這並不意味著我們不會在某個時間點進行潛在的地理合作。誰知道呢，但我們很樂意自己承擔 CVOT 風險。這就是我們現在的計劃。

Our next question comes from Edward Tenthoff Of Piper Sandler.

我們的下一個問題來自 Piper Sandler 的 Edward Tenthoff。

Great. Summer is going on and excited about the progress. As we look at the pipeline, what should we be expecting from C3? I know, that we're in these patient cohorts now of C3 glomerulopathy and maybe IgA nephropathy. When could we get data from those, and what would be your ultimate view for advancing ARO-C3further?

偉大的。夏天即將來臨，我們對進展感到興奮。當我們審視管道時，我們應該對 C3 有何期待？我知道，我們現在屬於 C3 腎小球病和 IgA 腎病患者隊列。我們什麼時候可以從中獲得數據？您對進一步推進 ARO-C3 的最終看法是什麼？

James?

詹姆士？

Yes. In terms of when we should get data, we're probably looking at end of next year, so end of 2024. And what was the other part of the question?

是的。至於我們應該何時獲取數據，我們可能會考慮到明年年底，即 2024 年底。問題的另一部分是什麼？

Just how would you anticipate progressing from there?

您預計接下來的進展如何？

Yes. I mean, I think it depends on what the data show us. I think there are several other examples out there of Phase 3 programs that are ongoing for IgA nephropathy and C3 glomerulopathy with biomarkers as primary endpoints. So I think our late-stage programs would probably look something similar to those.

是的。我的意思是，我認為這取決於數據向我們展示的內容。我認為還有其他幾個正在進行的 IgA 腎病和 C3 腎小球病 3 期項目的例子，以生物標誌物作為主要終點。所以我認為我們的後期項目可能看起來與那些類似。

Our next question comes from Mani Foroohar of Leerink Partners.

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

A quick 1 around how you think about building the CV side of the franchise. Could you lay out what your estimation is for what that CVOT should cost? I'm probably cascaded now. Given that you plan to go it alone, I would assume that you've got a reasonable budget estimate for what that might cost. And can you walk us through sort of how we should think about sort of expansion and OpEx as you build out the infrastructure to support what will be a larger study than you guys have ever done stand-alone before?

快速了解一下您如何看待建立特許經營權的簡歷方面。您能否列出您對 CVOT 成本的估計？我現在可能已經崩潰了。鑑於您打算單獨行動，我假設您已經對可能的成本有了合理的預算估計。您能否向我們介紹一下，當您構建基礎設施以支持比你們以前獨立完成的更大規模的研究時，我們應該如何考慮擴展和運營支出？

Sure. So we can't give you -- yes, we are putting together estimates about what that's going to cost. However, we still haven't had our end of Phase 2 meeting with the FDA. We are putting together our proposal. And so I expect that. we'll be speaking with them this year. Until we have that conversation, until we have feedback from them, it's going to be very difficult for us to give you good numbers just because, because we want better clarity. We will be happy to give you some estimates, some guidance, once we have those discussions. But at this point, it's a bit premature.

當然。所以我們不能給你——是的，我們正在對這將要花費的費用進行匯總。然而，我們仍然沒有與 FDA 舉行第二階段會議。我們正在整理我們的建議。所以我希望如此。今年我們將與他們交談。在我們進行對話之前，在我們收到他們的反饋之前，我們很難僅僅因為我們想要更好的清晰度而給您提供好的數字。一旦我們進行了這些討論，我們將很樂意為您提供一些估計和一些指導。但目前來看，還為時過早。

Okay. So we should expect some -- like we should expect numerical guidance around that. Post the end of Phase 2 meeting, is that a reasonable expectation for us to have?

好的。所以我們應該期待一些——就像我們應該期待圍繞這一點的數字指導。第二階段會議結束後，這是我們的合理期望嗎？

Yes. I think that is reasonable. We need to have feedback from the FDA. We need to incorporate that into our plans and then have that filtered out into our budget. So sometime, you know, sometime over the next couple of quarters, we should have a good estimate for you and then we will be happy to chat about it at that point.

是的。我認為這是合理的。我們需要 FDA 的反饋。我們需要將其納入我們的計劃，然後將其納入我們的預算。因此，您知道，在接下來的幾個季度的某個時候，我們應該對您有一個很好的估計，然後我們會很樂意在那時討論它。

One moment for our next question. Next question comes from Mike Ulz of Morgan Stanley.

請稍等一下我們的下一個問題。下一個問題來自摩根士丹利的邁克·烏爾茲。

Maybe just a follow-up on the pulmonary program, specifically to the MMP7 program. Can you just remind us when we might see the initial clinical data there? And should the focus be just on target knockdown, or are there other data points that we should be focused on as well?

也許只是肺部計劃的後續行動，特別是 MMP7 計劃。您能提醒我們什麼時候可以看到初步的臨床數據嗎？重點應該只放在目標擊倒上，還是還有其他我們應該關注的數據點？

Yes. I think, so the -- as we had stated at the Analyst Day meeting, we really think the focus there should be on the patients, since those are the population that has up regulated MMP7 in the valve and in the serum. So that's what we'll be focusing on. We're still in the healthy volunteer component of the study. And so, we don't know how the patient cohorts will enroll just yet. Depending on enrollment, it's conceivable we could have some data by end of next year.

是的。我認為，正如我們在分析師日會議上所說，我們確實認為重點應該放在患者身上，因為這些人群的瓣膜和血清中的 MMP7 表達上調。這就是我們將關注的重點。我們仍處於研究的健康志願者部分。因此，我們還不知道患者群體將如何註冊。根據註冊情況，可以想像我們可以在明年年底之前獲得一些數據。

Our next question is from Mayank Mamtani of B. Riley Securities.

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

So maybe just on the FeNO high asthma patient cohorts that, you're just starting to enroll, could you clarify the dose levels being looked at and sort of what initial number of patients you -- intend to have before you may look to disclose something externally? And if you could comment, how this could be same or different relative to, your execution on the mild to moderate asthma MAD patient cohort. And then I have a quick follow-up.

因此，也許就您剛剛開始入組的 FeNO 高哮喘患者隊列而言，您能否澄清正在考慮的劑量水平以及您在可能希望披露某些內容之前打算接收的初始患者數量外部？如果您能評論一下，這與您對輕度至中度哮喘 MAD 患者隊列的執行有何相同或不同。然後我會進行快速跟進。

Sure. So there are the 2 highest dose levels as what we're looking at in the FeNO cohorts. So that's the 92 milligram and the 184 milligram at dose levels that we studied in the healthy volunteers. We'll investigate those doses in the FeNO cohorts as well. And we're doing a 16 per cohort. I don't, in terms of how many we'd have to have enrolled before we disclose data, I can't really give you a clear answer to that.

當然。因此，我們在 FeNO 隊列中觀察到了 2 個最高劑量水平。這就是我們在健康志願者中研究的 92 毫克和 184 毫克劑量水平。我們還將在 FeNO 隊列中研究這些劑量。我們每組做 16 個。我不知道，就我們在披露數據之前必須註冊多少人而言，我無法真正給你一個明確的答案。

Yes. So let's just assume that we'll disclose those once -- once those cohorts are, are complete. It wouldn't make much sense for us to, to feed that out, drips and draps. I think we'll wait until that study's over.

是的。因此，我們假設一旦這些群組完成，我們就會披露這些信息。對我們來說，通過滴水和蓋布來餵食它沒有多大意義。我想我們會等到研究結束。

Got it. And in terms of your asthma cohort data before the end of the year, could you just clarify that would you also include some valve bronchoscopy data also in addition to serum data on the higher dose levels? Could you just clarify that?

知道了。就今年年底前的哮喘隊列數據而言，您能否澄清一下，除了較高劑量水平的血清數據之外，您還會包括一些瓣膜支氣管鏡檢查數據嗎？你能澄清一下嗎？

The asthma patients actually don't undergo bronchoscopy, so we don't have a valve data from the asthma patients. It's only the only sRAGE measure we get is from the serum in the asthma patients.

哮喘患者實際上沒有接受支氣管鏡檢查，因此我們沒有哮喘患者的瓣膜數據。我們從哮喘患者的血清中獲得的唯一 sRAGE 測量值。

Got it. And just lastly, on the financials, the 2 milestones earned from GSK and the data could you just clarify how they will be sort of modeled on your P&L in terms of recorded revenue amortization schedule?

知道了。最後，在財務方面，葛蘭素史克獲得的兩個里程碑和數據您能否澄清一下，它們將如何根據記錄的收入攤銷計劃在您的損益表上進行建模？

So, those milestones have already been recorded in revenue. They are not amortized over time. We actually recorded those -- the quarter before last, we received the cash in this past quarter.

因此，這些里程碑已經記錄在收入中。它們不會隨著時間的推移而攤銷。我們實際上記錄了這些——上個季度，我們在上個季度收到了現金。

Next question comes from Ellie Merle of UBS.

下一個問題來自瑞銀集團的艾莉·梅爾。

Just a follow-up on the pulmonary patient cohort timing, I guess for RAGE, just where are you in the enrollment of those high-FeNO cohorts? I think you just mentioned you had 16 per cohort. And then for MUC5AC, I guess, where are you in enrollment of the asthma patient cohorts? And have you started enrolling in the COPD cohort? And then just for MUC5AC, what should we expect in terms of the timing of potential patient data there?

只是對肺部患者隊列時間的跟進，我想對於 RAGE，您在那些高 FeNO 隊列的註冊中處於什麼位置？我想您剛剛提到每個隊列有 16 個。然後，對於 MUC5AC，我想，您在哮喘患者隊列的招募中處於什麼位置？您已經開始加入慢性阻塞性肺病隊列了嗎？那麼對於 MUC5AC，我們對潛在患者數據的時間安排應該有何期待？

So on the FeNO-cohorts, those -- the amendments to add those cohorts, I think, are just -- they've been filed and so they're working their way through the various regulatory bodies and ethics committees. And we haven't enrolled any FeNO patients just yet. And then the MUC5AC patient cohorts were enrolling into the -- actually, all the cohorts are open. So that all of the asthma patient cohorts are currently open from MUC5AC. And we'd be looking, assuming enrollment goes well, probably having data mid to late next year as well.

因此，在 FeNO 群體中，我認為添加這些群體的修正案只是——它們已經提交，因此正在通過各個監管機構和道德委員會進行工作。我們還沒有招募任何 FeNO 患者。然後 MUC5AC 患者隊列正在註冊——實際上，所有隊列都是開放的。因此，所有哮喘患者隊列目前均從 MUC5AC 開放。假設招生進展順利，我們會關注，可能會在明年中後期獲得數據。

And then your last question, I believe, was on the COPD cohorts from MUC5AC, that's a similar situation to the FeNO cohorts we've got the amendments filed and so those are working their way through to get ethics and regulatory approval. So we'd expect to have those being enrolled later this year, aiming to have data maybe end of next year.

我相信，你的最後一個問題是關於 MUC5AC 的 COPD 隊列，這與 FeNO 隊列的情況類似，我們已經提交了修正案，因此這些隊列正在努力獲得道德和監管部門的批准。因此，我們預計將在今年晚些時候招募這些人，目標是在明年底獲得數據。

Next question is from William Pickering of Bernstein.

下一個問題來自伯恩斯坦的威廉·皮克林。

So on Adipose, you gave a really interesting update at the R&D Day, but you didn't disclose the target. I was wondering what the next steps on that program are and when we might learn more about it?

因此，在 Adipose 上，您在研發日提供了非常有趣的更新，但您沒有透露目標。我想知道該計劃的下一步是什麼以及我們什麼時候可以了解更多信息？

Yes. We have not disclosed targets. We are still in the early days a bit with Adipose. We are -- we have we have some ideas for our targets, but we are not prepared to show any more data there quite yet. My hope is that, you'll start to hear more about the clinical plan for Adipose in 2024.

是的。我們還沒有透露目標。我們的 Adipose 仍處於早期階段。我們對我們的目標有一些想法，但我們還沒有準備好展示更多數據。我希望，您將開始聽到更多有關 2024 年 Adipose 臨床計劃的信息。

Got it. And then on HeFH, it sounds like you've become less definitive on the path forward for ANG3 in that indication versus last year. I was wondering, if you could just talk about sort of what aspects of your thinking have evolved? And how sure you are that you will, in fact, take it forward to Phase 3?

知道了。然後在 HeFH 上，與去年相比，您對 ANG3 在該適應症中的前進道路似乎變得不那麼明確了。我想知道，您能否談談您的思維在哪些方面發生了演變？您有多確定您確實會將其推進到第三階段？

Yes. So I think the issue here is whether we can develop the indication of HeFH without a full cardiovascular outcome trial. And there is some presidents support there and some other ones. So we are working our way to understand if there is a subpopulation of HeFH that can be pushed forward into a regulatory path without the requirement of the cardiovascular outcome trial. So that's kind of where we are right now.

是的。所以我認為這裡的問題是我們是否可以在沒有完整的心血管結果試驗的情況下開發 HeFH 的適應症。那裡有一些總統的支持，也有其他一些總統的支持。因此，我們正在努力了解是否有一個 HeFH 亞群可以在不需要心血管結果試驗的情況下進入監管路徑。這就是我們現在的處境。

Next question is from Luca Issi from RBC Capital.

下一個問題來自 RBC Capital 的 Luca Issi。

And again, maybe circling back on RAGE, James or Javier, what are you hoping to see for the initial readout for FeNO? I understand, the follow-up will be short, but what levels do you anticipate at baseline? And what kind of reduction are you hoping to see there? Again, just trying to understand what the ability for initial success there?

再說一遍，也許回到 RAGE，James 或 Javier，您希望看到 FeNO 的初步讀數是什麼？我知道，後續行動會很短，但您預計基線水平是多少？您希望看到什麼樣的減少？再說一次，只是想了解一下取得初步成功的能力有哪些？

And then maybe, Ken, if I may. I think your prior 10-Q suggested that the bill the facility in Verona, Wisconsin was going to cost $200 million to $260 million. However, the 10-Q today suggested that number has gone up to $260 million, $280 million. One, is that correct? And if 2, what drove that change? Thanks so much.

然後也許吧，肯，如果可以的話。我認為您之前的 10-Q 表明威斯康星州維羅納工廠的賬單將花費 2 億至 2.6 億美元。然而，今天的 10-Q 報告顯示，這一數字已上升至 2.6 億美元、2.8 億美元。一、這樣說對嗎？如果是 2，是什麼推動了這種變化？非常感謝。

Ken, do you want to start that?

肯，你想開始嗎？

So we have seen certain cost increases as well as about a quarter of a delay in that project. So you will see that, that total cost comes in a bit higher than we had originally estimated. That's really it.

因此，我們看到了一定的成本增加以及該項目大約四分之一的延遲。所以你會發現，總成本比我們最初估計的要高一些。確實如此。

Yes. So Luca, we do have a good point of reference for the FeNO therapeutics effect and that's the dupilumab and tezepelumab programs in which they saw somewhere between 40% and 48% reduction, I think it's either going to call which one, but that's the RAGE that I think we believe will be convincing that the RAGE inhibition, it does work through the IL-13. So that's the range that we're seeing. I think the baseline is 20 and --

是的。 Luca，我們確實對 FeNO 治療效果有一個很好的參考點，那就是 dupilumab 和 tezepelumab 項目，他們看到了 40% 到 48% 的減少，我認為要么會調用哪一個，但這就是 RAGE我認為我們相信RAGE 抑制確實通過IL-13 起作用。這就是我們看到的範圍。我認為基線是 20 並且——

Greater than

比...更棒

Greater than 20 FeNO, and people with FeNO greater than 200. So it's the same population very much of those point of reference, if you will, studies, and we expect to see something similar.

FeNO 大於 20 的人，以及 FeNO 大於 200 的人。因此，如果您願意的話，研究的參考點很大程度上是相同的人群，我們預計會看到類似的情況。

Next question is from Brendan Smith of TD Cowen.

下一個問題來自 TD Cowen 的 Brendan Smith。

Maybe a couple of quick ones from us. First, I just wanted to ask actually about some of the CNS programs that you alluded to that you're going to kind of announce and bring it to the clinic over the next couple of years. Really, I guess, how are you kind of thinking about which indications to move there? Are you really thinking to focus more on final indications, given that the tissue is a little bit easier to get to or really what is kind of your strategy and deciding where to go there? Kind of just trying to understand, where you think is especially right for RNAi?

也許我們會提供一些快速的。首先，我實際上想問一下您提到的一些中樞神經系統項目，您將在未來幾年內宣布並將其帶到診所。真的，我想，您是如何考慮搬到那裡的跡象的？鑑於組織更容易獲得，您是否真的考慮更多地關注最終適應症，或者實際上您的策略是什麼並決定去哪裡？我只是想了解一下，您認為哪些地方特別適合 RNAi？

And then if I could, just really quickly, I wanted to ask a little bit more about kind of your financing plan. Obviously, you have a decent balance sheet for now. But I mean, to your point, you haven't raised equity in a few years, but you have a fair number of important readouts coming up and a lot of studies going on. So as we're kind of just looking at cash burn over the next few years, what really is kind of your strategy for the next 18, 24 months?

然後，如果可以的話，我想盡快詢問更多有關您的融資計劃的信息。顯然，您目前的資產負債表還不錯。但我的意思是，就你的觀點而言，你已經有幾年沒有籌集資金了，但你有相當多的重要數據即將發布，並且大量研究正在進行。因此，由於我們只是關注未來幾年的現金消耗情況，那麼您未來 18 個月、24 個月的戰略到底是什麼？

Sure. I'll take that, and then I'll let Javier and James take a prior one. So look, as I mentioned in the prepared remarks, partnering is really a cornerstone of our financing strategy. And so we are exploring a number of different options really as we speak that are important for us. There are also other avenues. We are also exploring the possibility of doing some specific product financing for APOC3. We know that's going to be a CVOT. We know that's going to be expensive. And we are exploring the cost of capital for financing that in return for some royalties on that product for some period of time, things of that nature. And I think that we can get a long way to our financing needs through those levers and we are looking to pull those levers certainly in the near to mid-term, I think it's important for us.

當然。我會接受這個，然後我會讓哈維爾和詹姆斯接受之前的一個。因此，正如我在準備好的發言中提到的，合作確實是我們融資戰略的基石。因此，我們正在探索許多對我們來說很重要的不同選擇。還有其他途徑。我們也在探索為APOC3做一些特定產品融資的可能性。我們知道這將是一個 CVOT。我們知道這會很昂貴。我們正在探索融資的資本成本，以換取一段時間內該產品的一些特許權使用費，這種性質的事情。我認為，通過這些槓桿，我們可以在很長一段時間內滿足我們的融資需求，我們希望在近中期肯定會拉動這些槓桿，我認為這對我們很重要。

And then in regards to the CNS targets, we're interested in targets that may involve the spinal cord, as you mentioned, but also targets in the cortex, we can get good knockdown in various parts of the cortex and we're looking at some targets in the deeper brain, although that can be a little bit more challenging to achieve the same level of knockdown.

然後就中樞神經系統目標而言，正如您提到的，我們對可能涉及脊髓的目標感興趣，但也對皮質中的目標感興趣，我們可以在皮質的各個部分獲得良好的擊倒，我們正在研究大腦深處的一些目標，儘管要實現相同水平的擊倒可能更具挑戰性。

And then we like -- as we do for other tissue types targets with a degree of genetic validation that are either genetically defined or have some level of genetic validation behind them and preferably a degree of clinical validation with other modalities that are out there that have shown success that we could follow-on.

然後我們喜歡——就像我們對其他組織類型目標所做的那樣，具有一定程度的基因驗證，這些目標要么是基因定義的，要么是經過一定程度的基因驗證，最好是與現有的其他模式進行一定程度的臨床驗證。展示了我們可以跟進的成功。

I'm showing no further questions at this time. I would now like to turn the conference back to Chris Anzalone for closing remarks.

我目前沒有提出任何進一步的問題。現在我想請克里斯·安扎龍 (Chris Anzalone) 致閉幕詞。

Thanks everyone for joining us today, and I hope you have an enjoyable summer, and we look forward to talking to you soon.

感謝大家今天加入我們，希望您度過一個愉快的夏天，我們期待很快與您交談。

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

好的。今天的電話會議到此結束。感謝您的參與。您現在可以斷開連接。