Arrowhead Pharmaceuticals Inc (ARWR) 2025 Q3 法說會逐字稿

Ladies and gentlemen. Welcome to the Arrowhead Pharmaceuticals conference call. (Operator Instructions) I will now hand the conference 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）我現在將會議交給 Arrowhead 投資者關係副總裁 Vince Anzalone。請繼續，文斯。

Thank you. Good afternoon, everyone. Thank you for joining us today to discuss Arrowhead's results for its fiscal 2025 third-quarter ended June 30, 2025. With us today from management are president and CEO Dr. Chris Anzalone, who will provide an overview; Dr. Bruce Given, Interim Chief Medical Scientist, who will provide an update on late-clinical and regulatory; Andy Davis, Senior Vice President and Head of the Global Cardiometabolic Franchise, who will provide an update on commercialization activities; Dr. James Hamilton, Chief Medical Officer and Head of R&D, who will discuss our earlier stage development programs; and Dan Apel, Chief Financial Officer, who will give a review of the financials.

謝謝。大家下午好。感謝您今天加入我們，討論 Arrowhead 截至 2025 年 6 月 30 日的 2025 財年第三季業績。今天與我們一起出席的管理層有總裁兼首席執行官 Chris Anzalone 博士，他將提供概述；代理首席醫學科學家 Bruce Given 博士將提供有關後期臨床和監管的最新信息；高級副總裁兼全球心臟代謝特許經營負責人 Andy Davis 將提供有關商業化活動的最新信息；首席醫療官兼研發負責人 James Hamilton 博士將討論我們早期的財務計劃審查我們早期的財務狀況。

Following management's prepared remarks, we will open the call to questions. 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.

在管理階層發表完準備好的發言後，我們將開始提問。在我們開始之前，我想提醒您，今天電話會議上發表的評論包含《1933 年證券法》第 27A 條和《1934 年證券交易法》第 21E 條所定義範圍內的某些前瞻性陳述。

All statements other than statements of historical fact are forward-looking statements and are subject to numerous risks and uncertainties that could cause actual results to differ materially from those expressed in any forward-looking statements.

除歷史事實陳述之外的所有陳述均為前瞻性陳述，並且受多種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。

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

有關這些風險和不確定性的更多詳細信息，請參閱我們的 SEC 文件，包括我們最近的 10-K 表年度報告和 10-Q 表季度報告。現在我想將電話轉給公司總裁兼執行長 Christopher Anzalone。克里斯？

Thanks, Vince. Good afternoon, everyone, and thank you for joining us today. Before discussing the progress we've made over the past quarter, I'd like to address questions surrounding our partnership with Sarepta Therapeutics. Sarepta has recently experienced high-profile setbacks in products and programs that are unrelated to those licensed from Arrowhead.

謝謝，文斯。大家下午好，感謝大家今天的參與。在討論我們在過去一個季度取得的進展之前，我想先回答一下有關我們與 Sarepta Therapeutics 合作的問題。Sarepta 最近在與 Arrowhead 授權產品無關的產品和專案上遭遇了重大挫折。

Nevertheless, the situation has negatively affected our stock price, so I'd like to talk about what we think is important from an Arrowhead shareholder perspective. Sarepta recently announced a strategic restructuring plan that includes cost-cutting measures and a pipeline review that prioritizes funding, development, and commercialization of the programs the company licensed from Arrowhead.

儘管如此，這種情況還是對我們的股價產生了負面影響，所以我想從 Arrowhead 股東的角度談談我們認為重要的事情。Sarepta 最近宣布了一項策略重組計劃，其中包括削減成本措施和產品線審查，優先考慮該公司從 Arrowhead 獲得許可的專案的資金、開發和商業化。

Sarepta management has clearly stated that it believes this represents the future of the company. This gives us confidence that Sarepta will continue to meet its financial development and commercial obligations under the agreement.

Sarepta 管理層已明確表示，他們相信這代表著公司的未來。這使我們相信 Sarepta 將繼續履行協議規定的財務發展和商業義務。

The collaboration is continuing to operate as expected, which is, of course, a good thing for Arrowhead. It represents a source of capital to fund internal programs, platforms, and commercial build-out while ensuring the assets licensed to Sarepta are developed and commercialized.

此次合作正在按預期繼續進行，這對 Arrowhead 來說當然是一件好事。它代表著為內部項目、平台和商業建設提供資金的來源，同時確保授權給 Sarepta 的資產得到開發和商業化。

Should Sarepta fail to meet its obligations, the agreement has clear termination provisions that, in our view, would cause potentially valuable assets and associated intellectual property to be returned to Arrowhead, without Arrowhead having to repay any of the capital we have received from Sarepta.

如果 Sarepta 未能履行其義務，協議中有明確的終止條款，我們認為，這將導致潛在有價值的資產和相關知識產權返還給 Arrowhead，而 Arrowhead 不必償還我們從 Sarepta 獲得的任何資本。

That would also be an acceptable outcome. Let's now move on to our progress in the recent period. The biotech market has been challenging over the past several years, but we have no control over the broader sentiments. What we can control is our drive to serve patients and create shareholder value.

這也是可以接受的結果。現在讓我們來談談我們最近一段時間的進展。過去幾年，生技市場充滿挑戰，但我們無法控制整體情緒。我們能夠控制的是服務病患和創造股東價值的動力。

We view these broadly as three interrelated mandates, to create value, to create novel medicines capable of real impacts on human health, to generate the capital to fund development of them, and to build an engine to drive the growth of both.

我們將其概括為三個相互關聯的任務：創造價值、創造能夠對人類健康產生真正影響的新藥、籌集資金來資助其開發、以及建立一個引擎來推動兩者的成長。

We made important progress in all these areas during the recent period. Let's begin with development. This is clearly led by Plozasiran. We continue to have productive interactions with regulators in the US and Europe about our market authorization applications and treatments of FCS, and we look forward to our November 18 US PDUFA date. We are also on track with commercial build-out, and our complete team is nearly assembled to support the FCS launch.

近期我們在這些領域都取得了重要進展。讓我們從開發開始。這顯然是由 Plozasiran 主導的。我們繼續與美國和歐洲的監管機構就我們的市場授權申請和 FCS 治療進行富有成效的互動，我們期待 11 月 18 日美國 PDUFA 的日期。我們的商業建設也正在按計劃進行，我們的整個團隊幾乎已經組成完畢，可以支援 FCS 的發布。

Further, we achieved full enrollment in SHASTA-3, SHASTA-4, and MUIR-3, Arrowhead's Phase 3 studies designed to support regulatory submissions for plozasiran in the treatment of severe hypertriglyceridemia or sHTG.

此外，我們還完成了 SHASTA-3、SHASTA-4 和 MUIR-3 的全面招募，這些是 Arrowhead 的 3 期研究，旨在支持 plozasiran 在治療嚴重高三酰甘油血症或 sHTG 方面的監管提交。

These studies enrolled approximately 2,200 patients in 24 countries in a very short period of time. The primary endpoint is focused on triglyceride reduction at 12 months. So with full enrollment reached in June 2025, we are on track for study completion by mid-2026.

這些研究在很短的時間內招募了來自 24 個國家的約 2,200 名患者。主要終點是關注 12 個月時的三酸甘油酯降低情況。因此，隨著 2025 年 6 月達到全部入學人數，我們預計在 2026 年中期完成研究。

Zodasiran, Arrowheads' candidate designed to reduce expression of ANGPTL3, is being developed as a potential treatment for homozygous familial hypercholesterolemia or HoFH, a rare genetic condition that leads to severely elevated LDL-cholesterol and early onset cardiovascular disease.

Zodasiran 是 Arrowheads 公司為降低 ANGPTL3 表現而設計的候選藥物，目前正在開發作為純合家族性高膽固醇血症 (HoFH) 的潛在治療方法，HoFH 是一種罕見的遺傳疾病，會導致 LDL 膽固醇嚴重升高和早發性心血管疾病。

We initiated the YOSEMITE Phase 3 study and enrolled the first patients in July. Approximately 60 subjects over the age of 12 will be randomized to receive four quarterly doses of 200 milligrams of zodasiran or placebo.

我們啟動了 YOSEMITE 第三階段研究，並在 7 月招募了第一批患者。大約 60 名 12 歲以上的受試者將隨機分配接受每季四次劑量的 200 毫克 zodasiran 或安慰劑。

The primary endpoint of YOSEMITE is the percent change in LDL-cholesterol from baseline to month 12. We think that given our Phase 2 data, this feels like a relatively low-risk Phase 3, potentially enabling a commercial opportunity that overlays well with the team we are building for plozasiran. Therefore, with a relatively small investment in a one-year 60-subject Phase 3 study, we see an opportunity to extract more value from the commercial infrastructure we are already building.

YOSEMITE 的主要終點是從基線到第 12 個月的 LDL 膽固醇百分比變化。我們認為，根據我們的第 2 階段數據，這感覺像是一個相對低風險的第 3 階段，可能會帶來與我們為 plozasiran 建立的團隊良好重疊的商業機會。因此，透過對為期一年、涉及 60 個物件的第三階段研究進行相對較小的投資，我們看到了從已經正在建造的商業基礎設施中獲取更多價值的機會。

Beyond plozasiran and zodasiran, there are two additional investigational RNAi based candidates developed by Arrowhead that are currently in late-stage pivotal studies. Fazirsiran, being developed for alpha-1 antitrypsin liver disease, is partnered with Takeda.

除了 plozasiran 和 zodasiran 之外，Arrowhead 還開發了另外兩種基於 RNAi 的候選藥物，目前正處於後期關鍵研究中。Fazirsiran 正在與武田公司合作開發，用於治療 α-1 抗胰蛋白酶肝病。

Arrowhead retains 50/50 profit share in the US, 20%, 25% royalties outside the US, and up to $527.5 million of remaining regulatory and five commercial milestones. Takeda has guided that it's Phase 3 study could be fully enrolled this year, and the study has a primary endpoint at two years.

Arrowhead 在美國保留 50/50 的利潤份額、20% 的利潤份額、美國以外地區保留 25% 的專利費，以及高達 5.275 億美元的剩餘監管和五個商業里程碑。武田公司表示，其第三階段研究可能在今年全面招募受試者，研究的主要終點為兩年。

Olpasiran, being developed for ASCVD, is licensed to Amgen, which announced that its Phase 3 cardiovascular outcomes trial was fully enrolled in the first half of 2024. We are eligible for up to $485 million of remaining milestones related to this program.

Olpasiran 正在為 ASCVD 開發，已授權給安進公司，該公司宣布其 3 期心血管結果試驗已於 2024 年上半年全面招募患者。我們有資格獲得與該計劃相關的最高 4.85 億美元的剩餘里程碑。

I highlight these four late-stage drug candidates because we expect them to be substantial value drivers in the near to mid-term. They also set up the possibility of multiple launches between November 2025 and the end of 2028.

我重點介紹這四種後期候選藥物，因為我們預期它們將在近期至中期內成為重要的價值驅動因素。他們也設定了 2025 年 11 月至 2028 年底期間多次發射的可能性。

As we've discussed in the past, plozasiran and our other late-stage drug candidates together form the basis of our near-term value proposition. But these are enhanced by several programs underneath them, all of which made good progress in the recent period.

正如我們過去所討論過的，plozasiran 和我們的其他後期候選藥物共同構成了我們近期價值主張的基礎。但這些都得到了其下的幾個項目的加強，所有這些項目在最近一段時間都取得了良好的進展。

Broadening out the cardiometabolic franchise are our first two obesity candidates, ARO-INHBE and ARO-ALK7. ARO-INHBE began a Phase 1/2 study early in the year, and we recently announced that we dosed the first subjects in a Phase 1/2 clinical trial of ARO-ALK7, which we believe is the first investigational RNAi therapeutic to enter clinical studies targeting adipose tissue.

擴大心臟代謝特許經營權的是我們的首批兩種肥胖候選藥物 ARO-INHBE 和 ARO-ALK7。ARO-INHBE 於今年年初開始了 1/2 期研究，我們最近宣佈在 ARO-ALK7 的 1/2 期臨床試驗中對首批受試者進行了給藥，我們相信這是第一個進入針對脂肪組織臨床研究的試驗性 RNAi 療法。

We expect to have initial, early datasets for both candidates at the end of the year. Expanding the cardiometabolic franchise, we expect to reach the clinic this year for what we believe will be the first RNAi dimer in clinical studies.

我們預計將在今年年底獲得兩位候選人的初步早期數據集。透過擴大心臟代謝特許經營權，我們預計今年將進入臨床研究階段，我們相信這將是臨床研究中第一個 RNAi 二聚體。

It is designed to reduce expression of both PCSK9 and APOC3, and could be a powerful agent in the treatment of ASCVD in patients with mixed hyperlipidemia. There is substantial unmet medical need in this large patient population and we should have a good idea how well this drug candidate lowers LDL-c and triglycerides in 2026.

它旨在降低 PCSK9 和 APOC3 的表達，並可能成為治療混合性高脂血症患者 ASCVD 的強效藥物。這一龐大的患者群體中存在大量未滿足的醫療需求，我們應該對這種候選藥物在 2026 年降低 LDL-c 和三酸甘油酯的效果有一個很好的了解。

We continue to make good progress in manufacturing, toxicology studies, and clinical trial planning, and we are on track to file a CTA in the coming months. Our burgeoning, systemically-delivered, CNS franchise is also a potential near to mid-term value driver. Should this platform translate from primates to humans, we think it would represent a transformational leap forward in CNS therapies.

我們在製造、毒理學研究和臨床試驗規劃方面繼續取得良好進展，並預計在未來幾個月內提交 CTA。我們蓬勃發展、系統交付的 CNS 特許經營權也是潛在的近期至中期價值驅動因素。如果該平台從靈長類動物推廣到人類，我們認為它將代表中樞神經系統治療的一次變革性飛躍。

Importantly, later this year we expect to file a CTA for ARO-MAPT, our wholly-owned candidate against Alzheimer's disease and various Tauopathies. We are hopeful that we can achieve initial proof of concept with this platform and candidate as early as late 2026.

重要的是，我們預計將於今年稍後提交 ARO-MAPT 的 CTA，ARO-MAPT 是我們全資擁有的阿茲海默症和各種 Tauopathies 的候選藥物。我們希望最早能在 2026 年底透過該平台和候選人實現初步概念驗證。

Beyond these, we have a wealth of other clinical-stage programs to drive longer-term value and serve as sources of capital through business development. In fact, we are on track to meet our [20] in '25 initiative whereby we would have 20 individual drug candidates in clinical studies or at market by the end of 2025. Nine of these are partnered.

除此之外，我們還有大量其他臨床階段項目來推動長期價值並透過業務發展作為資金來源。事實上，我們預計將實現「2025 年 20 個」計劃，即到 2025 年底，我們將有 20 種候選藥物進入臨床研究或上市。其中九家是合作夥伴。

The 11 wholly-owned clinical candidates serve as potential partnering targets and provide value redundancy for our other programs, and we expect several data readouts through the end of the year. Together, these give us a tremendous amount of ammunition to create value.

這 11 家全資臨床候選公司是潛在的合作目標，為我們的其他項目提供了價值冗餘，我們預計到今年年底將有幾份數據讀數。這些共同為我們創造價值提供了巨大的彈藥。

This brings us to the second important component of building durable value, an adequate source of financing independent on the capital markets. We currently have a strong balance sheet relative to our needs over the next few years. In addition, we have made important progress sourcing new capital in the recent period.

這為我們帶來了建構持久價值的第二個重要要素，即獨立於資本市場的充足融資來源。相對於未來幾年的需求，我們目前的資產負債表強勁。此外，我們近期在尋找新資本方面取得了重要進展。

We announced that our Visirna Therapeutics majority-owned subsidiary signed an asset purchase agreement whereby Sanofi will acquire rights to develop and commercialize plozasiran as a potential treatment for FCS and SHTG in Greater China.

我們宣布，我們擁有多數股權的子公司 Visirna Therapeutics 簽署了一項資產購買協議，賽諾菲將根據該協議獲得在大中華區開發和商業化 plozasiran 作為 FCS 和 SHTG 潛在治療方法的權利。

Visirna will receive an upfront payment of $130 million and be eligible to receive milestone payments of up to $265 million upon approval of plozasiran in FCS and SHTG in mainland China. Arrowhead is further eligible to receive royalties on net commercial product sales in Greater China as part of the Arrowhead-Visirna license which was assigned in part to Sanofi.

Visirna 將獲得 1.3 億美元的預付款，並且當 plozasiran 在中國大陸的 FCS 和 SHTG 獲得批准後，Visirna 有資格獲得高達 2.65 億美元的里程碑付款。作為 Arrowhead-Visirna 許可的一部分，Arrowhead 還有資格獲得大中華區淨商業產品銷售額的特許權使用費，該許可已部分轉讓給賽諾菲。

When we co-founded Visirna in 2022, we saw greater China as an important, but undervalued, potential future market for multiple programs in Arrowhead's pipeline. We licensed Chinese rights for plozasiran, zodasiran, and ARO-HSD to Visirna, which received outside funding to support development.

當我們在 2022 年共同創立 Visirna 時，我們將大中華區視為 Arrowhead 多個專案的重要但被低估的潛在未來市場。我們將 plozasiran、zodasiran 和 ARO-HSD 的中國權利授權給 Visirna，該公司獲得了外部資金來支持開發。

Sanofi has a strong presence in China and is well positioned to assume commercialization of plozasiran, should it be approved by Chinese regulatory authorities. We did not use any Arrowhead funds to advance China specific development or regulatory activities, and upon closing we will own approximately 56% of Visirna.

賽諾菲在中國擁有強大的影響力，如果獲得中國監管機構的批准，它將完全有能力承擔 plozasiran 的商業化。我們沒有使用任何 Arrowhead 基金來推進中國特定的開發或監管活動，交易完成後我們將擁有 Visirna 約 56% 的股份。

There are tax considerations and other costs, but we ultimately expect to realize a sizable amount from this deal. We hope that over time we may monetize Chinese rights to zodasiran and ARO-HSD in a similar fashion.

雖然有稅收考慮和其他成本，但我們最終希望從這筆交易中獲得可觀的收益。我們希望隨著時間的推移，我們可以以類似的方式將 zodasiran 和 ARO-HSD 的中國版權貨幣化。

The next key capital-building event I want to mention is reaching the first of two prespecified enrollment targets in a Phase 1/2 clinical study of ARO-DM1 for the treatment of type 1 myotonic dystrophy, which is partnered with Sarepta.

我想提到的下一個關鍵資本建構事件是達到 ARO-DM1 用於治療 1 型強直性肌肉失養症的 1/2 期臨床研究中兩個預定入組目標中的第一個，該研究與 Sarepta 合作進行。

Reaching this milestone triggered a $100 million payment, which is due from Sarepta within 8 60 days of when it was earned. We believe we are on track to meet the second enrollment target at the end of the year, which would trigger an additional $200m payment.

達到這一里程碑將觸發 1 億美元的付款，Sarepta 應在付款後的 8 至 60 天內支付這筆款項。我們相信，我們預計在今年年底實現第二次招生目標，這將帶來額外的 2 億美元付款。

Our large pipeline and expectation that we have cash into fiscal 2028 suggest that we have the first two categories of value creation under control. This leads us to the third priority, creating an engine to drive the growth of both.

我們擁有龐大的管道，並且預計到 2028 財年我們仍有足夠的現金，這表明我們已經掌控了前兩類價值創造。這就引出了我們的第三個優先事項，即創建一個推動兩者成長的引擎。

I think it is rather clear that we have built this as well. We are now able to address gene targets in five different areas, hepatocytes, pulmonary, adipose, skeletal muscle, and CNS. We also believe we are capable of silencing two genes with a single molecular entity using our dimer technology.

我認為很明顯我們也已經建立了這個。我們現在能夠解決五個不同領域的基因目標，即肝細胞、肺、脂肪、骨骼肌和中樞神經系統。我們也相信，我們能夠利用二聚體技術透過單一分子實體沉默兩個基因。

This gives us broad reach to go where disease is, and, coupled with our expectation of introducing three to four new drug candidates into clinical studies every year, we expect to continue to grow our ability to impact human health very rapidly.

這使我們能夠廣泛地接觸到疾病所在的地方，再加上我們預計每年將三到四種新的候選藥物投入臨床研究，我們預計將繼續快速增強我們影響人類健康的能力。

This also reads on our ability to continue to access significant capital through business development before and after achieving substantial product revenue. Ultimately, we are doing all of this to bring important medicines to the patients who need them, and this does not happen without careful preparation. We are building a right-sized commercial organization staffed with what we think are the top people in the field with extensive experience in cardiometabolic and rare disease.

這也顯示我們在獲得大量產品收入之前和之後透過業務發展繼續獲取大量資本的能力。最終，我們所做的一切都是為了將重要的藥物送到需要的患者手中，而這一切都離不開精心的準備。我們正在建立一個規模合適的商業組織，其成員都是我們認為的該領域頂尖人才，在心臟代謝和罕見疾病方面擁有豐富的經驗。

We've made strong progress in market access, analytics, operations, marketing, and building a commercial sales team. US launch preparations are now if full swing for plozasiran in FCS, and we intend to be launch ready even before our PDUFA date on November 18.

我們在市場准入、分析、營運、行銷和商業銷售團隊建立方面取得了長足的進展。美國目前正在全力籌備 plozasiran 在 FCS 的上市事宜，我們計劃在 11 月 18 日 PDUFA 日期之前做好上市準備。

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

了解上述概述後，我現在想將電話交給 Bruce Given。布魯斯？

Thanks, Chris. And good afternoon, everyone. Since we last spoke, we've continued the forward momentum in our development of plozasiran to treat FCS and severe hypertriglyceridemia. Our US NDA to support FCS treatment was submitted last year, and our PDUFA date is November 18, 2025.

謝謝，克里斯。大家下午好。自從我們上次交談以來，我們繼續推進 plozasiran 的開發，以治療 FCS 和嚴重的高三酸甘油酯血症。我們去年提交了支持 FCS 治療的美國 NDA，我們的 PDUFA 日期是 2025 年 11 月 18 日。

Filings in Europe, Australia, and Canada are all progressing as well. We are reassured that the cadence of our interactions with US and global regulators has not changed, nor have any expectations of adhering to established timelines. Two months ago, we completed enrollment in our SHASTA severe hypertriglyceridemia development program well ahead of expectations.

歐洲、澳洲和加拿大的申請也都在進展中。我們確信，我們與美國和全球監管機構互動的節奏沒有改變，也沒有遵守既定時間表的期望。兩個月前，我們提前完成了 SHASTA 嚴重高三酸甘油酯血症發展計畫的招募。

The SHASTA program is comprised of SHASTA-3 and SHASTA-4, two adequate and well-controlled trials designed to meet the statutory requirement of evidence for effectiveness. Along with the supportive MUIR-3 trial in mixed hyperlipidemia, which provides additional safety data in a relevant patient population to satisfy regulatory requirements for a complete file.

SHASTA 計劃由 SHASTA-3 和 SHASTA-4 組成，這兩項充分且控制良好的試驗旨在滿足有效性證據的法定要求。結合混合性高脂血症的支持性 MUIR-3 試驗，該試驗在相關患者群體中提供了額外的安全數據，以滿足完整文件的監管要求。

The sizing of the Phase 3 SHASTA-3 and 4 studies was informed by the needs of regulatory authorities to demonstrate safety while confirming the efficacy suggested by the Phase 2 SHASTA-2 trial, where the primary endpoint of difference in triglycerides at week 24 compared to baseline for the 25-milligram dose was minus 53%, with a p-value less than 0.0001, which was accompanied by a numerical decrease in adjudicated events of acute pancreatitis.

確定 3 期 SHASTA-3 和 4 研究的規模是根據監管機構的需要而定的，即證明安全性，同時確認 2 期 SHASTA-2 試驗所建議的有效性，其中 25 毫克劑量組第 24 週甘油三酯與基線相比的差異的主要終點為-53%，p 值小於 0.0001，同時伴隨急性胰臟炎的急性事件伴隨急性因素減少。

The two SHASTA Phase 3 trials are similarly designed, totaling around 700 patients, and are very highly powered to demonstrate statistically significant improvement in triglycerides with 25 milligrams of plozasiran compared with placebo over twelve months of treatment.

兩項 SHASTA 第三階段試驗的設計類似，總共涉及約 700 名患者，並且非常有力地證明，與安慰劑相比，經過十二個月的治療，25 毫克 plozasiran 可顯著改善三酸甘油酯水平。

After accounting for randomization allocation in the SHASTA studies, the placebo-controlled double-blind MUIR-3 study was designed to demonstrate statistically significant improvement in triglycerides with 25 milligrams of plozasiran compared with placebo over 12 months of treatment, and is also expected to achieve a high level of significance while primarily serving to enhance the safety database for the SHTG filing. Assuming positive data, these three separate Phase 3 studies should support our planned sNDA filing for SHTG in 2026.

在考慮了 SHASTA 研究中隨機分配之後，安慰劑對照的雙盲 MUIR-3 研究旨在證明，與安慰劑相比，經過 12 個月的治療，25 毫克 plozasiran 可顯著改善甘油三酯水平，並且預計也將達到較高的顯著性水平，同時主要用於增強 SHTG 備案的安全數據庫。假設數據為陽性，這三個獨立的 3 期研究應該支持我們計劃於 2026 年為 SHTG 提交 sNDA。

Although SHASTA-3 and 4 were not prospectively designed to be outcome studies, given the sizing of the combined studies and the observed event rate in the SHASTA-2 study, we hope to observe at least a favorable trend in plozasiran's documented acute pancreatitis within the studies.

儘管 SHASTA-3 和 4 並非前瞻性設計為結果研究，但考慮到合併研究的規模和 SHASTA-2 研究中觀察到的事件發生率，我們希望在研究中觀察到 plozasiran 記錄的急性胰臟炎至少呈現有利趨勢。

However, the SHTG program also features a unique outcome study named SHASTA-5, designed to directly assess the ability of plozasiran to reduce the time to first event of positively adjudicated acute pancreatitis in high-risk SHTG patients.

然而，SHTG 計劃還具有一項名為 SHASTA-5 的獨特結果研究，旨在直接評估 plozasiran 縮短高風險 SHTG 患者首次確診急性胰臟炎的時間的能力。

While it is possible that this trial will be submitted to regulatory agencies for possible inclusion in labeling, the primary audience and impetus for this study is actually national health technology assessment organizations.

雖然這項試驗可能會提交給監管機構以便納入標籤，但這項研究的主要受眾和動力實際上是國家衛生技術評估組織。

On the basis of observational data demonstrating the causal link between elevated triglycerides and risk of pancreatitis, and observed effects of plozasiran in SHTG patients, it is expected that less than 150 patients will be recruited to accrue sufficient events in this outcome study.

根據證明三酸甘油酯升高與胰臟炎風險之間的因果關係的觀察數據，以及在 SHTG 患者中觀察到的 plozasiran 的影響，預計本結果研究將招募不到 150 名患者來累積足夠的事件。

We look forward to presenting more details on the design and rationale of this study at an upcoming major medical meeting. The broader cross-functional cardiometabolic clinical team has been present at key medical congresses this past quarter, including ENDO, National Lipid Association, and the American Society of Preventive Cardiology. We continue to share new data to demonstrate the value of plozasiran, and the reception from the scientific and clinical communities has been engaged and enthusiastic.

我們期待在即將舉行的大型醫學會議上提供有關這項研究的設計和基本原理的更多細節。上個季度，更廣泛的跨職能心臟代謝臨床團隊出席了重要的醫學會議，包括 ENDO、國家脂質協會和美國預防心臟病學會。我們不斷分享新數據來證明plozasiran的價值，科學界和臨床界對此反應熱烈。

Turning our attention to zodasiran, another genetically validated RNAi drug designed to reduce expression of angiopoietin protein-like 3 or ANGPTL3, is now in development for the treatment of homozygous familial hypercholesterolemia, a rare genetic disorder characterized by exceptionally high LDL cholesterol levels due to very low or absent LDL receptor function.

將我們的注意力轉向 zodasiran，這是另一種經過基因驗證的 RNAi 藥物，旨在降低血管生成素蛋白樣 3 或 ANGPTL3 的表達，目前正在開髮用於治療純合家族性高膽固醇血症，這是一種罕見的遺傳性疾病，其特徵是由於 LDL 受體功能非常低或缺失而導致 LDL 膽固醇水平極高。

The results of GATEWAY, our open-label Phase 2 study in this population, were presented this year at the European Atherosclerosis Society and showed robust and durable reduction in LDL-C and other atherogenic lipoproteins. The efficacy results were similar to those of evinacumab, a monoclonal antibody against ANGPTL3, that requires monthly infusions, but with plozasiran, the dosing is convenient quarterly subcutaneous dosing.

我們針對該族群進行的開放標籤 2 期研究 GATEWAY 的結果今年在歐洲動脈粥樣硬化學會上公佈，結果顯示 LDL-C 和其他致動脈粥樣硬化脂蛋白強勁且持久地降低。其療效結果與 evinacumab（一種針對 ANGPTL3 的單株抗體）相似，後者需要每月輸注，但使用 plozasiran 時，給藥方式為每季一次皮下給藥，十分方便。

We are pleased to report YOSEMITE, the Phase 3 study of zodasiran in HoFH, began earlier this year, and the first patient was randomized last month. Assuming successful demonstration of safety and efficacy, data from YOSEMITE could support regulatory filings for zodasiran as early as 2028 or 2029.

我們很高興地報告，針對純合子家族性高膽固醇血症 (HoFH) 的 zodasiran 的 3 期研究 YOSEMITE 已於今年早些時候啟動，並於上個月對第一位患者進行了隨機分組。假設成功證明安全性和有效性，YOSEMITE 的數據最早可在 2028 年或 2029 年支持 zodasiran 的監管備案。

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

現在我將電話轉給安迪戴維斯。安迪？

Thank you, Bruce. The FDA PDUFA date for plozasiran set for November 18 is now less than four months away, and I'm pleased to report that our commercialization preparations are fully on track. When I last updated you in May, we were in the midst of building out our commercial sales organization.

謝謝你，布魯斯。FDA 為 plozasiran 頒發 PDUFA 日期定於 11 月 18 日，現在距離該日期還有不到四個月的時間，我很高興地報告，我們的商業化準備工作正在全面推進。當我上次在五月向您更新情況時，我們正處於建立商業銷售組織的過程中。

I'm proud to share that as of this month, our national sales leader, full team of regional sales leaders, and fit-for-purpose field force of rare disease specialists are now on board and undergoing training. By the end of this month, the team will begin engaging with key healthcare professionals, advancing FCS disease education in preparation for launch.

我很自豪地告訴大家，從本月起，我們的全國銷售領導、整個區域銷售領導團隊以及適合用途的罕見疾病專家現場團隊現已加入並接受培訓。到本月底，團隊將開始與主要醫療保健專業人員接觸，推動 FCS 疾病教育，為啟動做準備。

Our market access team continues to execute exceptionally well against our preapproval information exchange strategy. To date, we've connected with payers representing over 85% of US covered lives, delivering compelling data on the clinical value and anticipated profile of plozasiran.

我們的市場准入團隊繼續出色地執行我們的預先批准資訊交換策略。迄今為止，我們已經與代表美國 85% 以上受保人群的付款人建立了聯繫，並提供了有關 plozasiran 臨床價值和預期概況的令人信服的數據。

We remain highly encouraged by payer interest, particularly in plozasiran's potential to deeply lower triglycerides, support achievement of guideline-directed goals, namely less than 500 milligrams per deciliter, and significantly reduce the risk of acute pancreatitis.

我們仍然對付款人的興趣感到非常鼓舞，特別是對 plozasiran 大幅降低三酸甘油酯、支持實現指南指導目標（即每分升低於 500 毫克）以及顯著降低急性胰臟炎風險的潛力。

We're also seeing positive developments in the FCS landscape, which reinforce our confidence heading into launch. The significant unmet need in the FCS community is clear and acknowledged by both payers and providers.

我們也看到 FCS 領域出現了積極的發展，這增強了我們對發布的信心。FCS 社群中存在著顯著的未滿足需求，這一點已得到付款方和提供者雙方的認可。

On the payer front, dynamics appear to be favorable, with access being granted to both genetically confirmed patients and those patients satisfying the diagnostic scoring tools designed to discriminate with SHTG from those whose signs, symptoms, and medical history mimic genetic FCS.

在付款人方面，動態似乎是有利的，已確診的患者和滿足診斷評分工具的患者均可獲得治療，這些工具旨在區分 SHTG 患者和體徵、症狀和病史類似於遺傳性 FCS 的患者。

This is especially motivating given that plozasiran is currently the only APOC3 inhibitor to demonstrate clinical results in both genetic and clinical FCS in a Phase 3 registrational study. And from a provider perspective, the specialty mix we're observing, preventative cardiologists, endocrinologists, and lipidologists is exactly what we anticipated and aligns well with our launch targeting strategy.

鑑於 plozasiran 目前是唯一在 3 期註冊研究中證明在遺傳和臨床 FCS 方面均有臨床效果的 APOC3 抑制劑，這一點尤其令人鼓舞。從提供者的角度來看，我們觀察到的專業組合，預防心臟病專家、內分泌學家和脂質學家正是我們預期的，並且與我們的發布目標策略非常一致。

In summary, we remain on schedule and energized by the opportunity to bring investigational plozasiran to individuals living with FCS and their families. We're excited for what plozasiran, a potential first-in-class siRNA therapy, could mean to those suffering from this difficult disease.

總而言之，我們仍在按計劃進行，並有機會將研究性的 plozasiran 帶給 FCS 患者及其家人，這讓我們充滿活力。我們很高興看到 plozasiran（一種潛在的首創 siRNA 療法）對患有這種難治疾病的人具有重大意義。

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

現在我將電話轉給詹姆斯·漢密爾頓。詹姆斯？

Thank you, Andy. I'd like to provide an overview and updates on several of our early-stage clinical and translational development programs. In obesity, our ARO-INHBE and ARO-ALK7 programs, targeting the activin pathway, are currently being investigated as treatments for obesity in Phase 1 studies.

謝謝你，安迪。我想概述並更新我們的幾個早期臨床和轉化開發項目。在肥胖症方面，我們針對激活素通路的 ARO-INHBE 和 ARO-ALK7 計畫目前正在進行第一階段研究，作為肥胖症的治療方法。

The INHBE study is currently enrolling multi-dose cohorts using ARO-INHBE in combination with tirzepatide. The ARO-ALK7 study is in the single-dose escalation phase, with multi-dose and combination cohorts opening soon. We anticipate sharing data from both the ALK7 and INHBE studies at the end of the year.

INHBE 研究目前正在招募使用 ARO-INHBE 與 tirzepatide 聯合治療的多劑量隊列。ARO-ALK7 研究目前處於單劑量遞增階段，多劑量和聯合隊列研究即將開放。我們預計將在今年年底分享 ALK7 和 INHBE 研究的數據。

Regarding our muscle clinical programs partnered with Sarepta, the ARO-DM1 Phase 1/2a study has completed the single-dose cohorts and is now enrolling multi-dose cohorts of patients with myotonic dystrophy.

關於我們與 Sarepta 合作的肌肉臨床項目，ARO-DM1 第 1/2a 期研究已經完成單劑量組，目前正在招募強直性肌肉營養不良症患者的多劑量組。

Similarly, the ARO-DUX4 Phase 1/2a study has nearly completed enrollment of single-dose cohorts, and the first year-long multi-dose cohort is open for enrollment. Consistent with previous guidance, we are on track for data availability by year-end.

同樣，ARO-DUX4 1/2a 期研究的單劑量隊列招募工作已接近完成，並且第一個為期一年的多劑量隊列招募工作已開放。與先前的指導一致，我們預計在年底前獲得數據。

However, timing on data release is determined by Sarepta. Our wholly-owned ARO-MAPT program is on track for submission of a CTA by year-end. As a reminder, ARO-MAPT uses subcutaneous administration of a novel siRNA delivery platform designed to deliver an siRNA targeting CNS tau protein expression across the blood-brain barrier.

不過，數據發布的時間由 Sarepta 決定。我們全資擁有的 ARO-MAPT 計劃預計將在年底前提交 CTA。提醒一下，ARO-MAPT 使用皮下注射一種新型 siRNA 遞送平台，旨在透過血腦屏障遞送針對中樞神經系統 tau 蛋白表達的 siRNA。

Tau aggregated into neurofibrillary tangles is believed to be one of the causative factors of Alzheimer's disease and is also causative of various other tauopathies. Nonclinical evaluations in monkeys with subcutaneous administration of ARO-MAPT using clinically translatable doses have shown better than 75% knockdown of tissue level of MAPT mRNA in the CNS.

聚集成神經纖維纏結的 Tau 被認為是阿茲海默症的致病因子之一，也是其他各種 Tau 蛋白質疾病的原因。使用臨床可轉化劑量對猴子進行皮下注射 ARO-MAPT 進行的非臨床評估表明，中樞神經系統 MAPT mRNA 組織水平的降低率超過 75%。

Importantly, monkey tissue level knockdown has translated into CSF tau protein reductions of better than 75% with duration of effect supportive of either monthly or potentially quarterly subcutaneous dose regimens. The monkey CSF tau protein knockdown data are an important translational step as we move this program towards the clinic. Full preclinical data will be presented at an upcoming scientific conference.

重要的是，猴組織層級的敲低已轉化為腦脊髓液 tau 蛋白減少超過 75%，且效果持續時間支持每月或每季皮下給藥方案。隨著我們將這個計畫推向臨床，猴子腦脊髓液 tau 蛋白敲低數據是一個重要的轉化步驟。完整的臨床前數據將在即將舉行的科學會議上公佈。

I will now turn the call over to Dan Appel.

現在我將電話轉給丹·阿佩爾 (Dan Appel)。

Thank you, James, and good afternoon, everyone. As we reported today, our net loss for the quarter ended June 30, 2025, was $175.2 million or a loss of $1.26 per share, based on 139 million fully diluted weighted average shares outstanding.

謝謝你，詹姆斯，大家下午好。正如我們今天所報告的，根據 1.39 億股完全稀釋加權平均流通股計算，截至 2025 年 6 月 30 日的季度淨虧損為 1.752 億美元，即每股虧損 1.26 美元。

This compares with a net loss of $170.8 million or a loss of $1.38 per share for the prior year quarter ended June 30, 2024, based on 124.2 million fully diluted weighted average shares outstanding in that prior year quarter. Revenue for the quarter ended June 30, 2025, was $27.8 million, driven almost entirely by the recognition of revenue related to our license and collaboration agreement with Sarepta.

相比之下，截至 2024 年 6 月 30 日的上一季淨虧損為 1.708 億美元，即每股虧損 1.38 美元，基於上一季 1.242 億股完全稀釋加權平均流通股。截至 2025 年 6 月 30 日的季度收入為 2,780 萬美元，幾乎完全來自與 Sarepta 簽訂的授權和合作協議相關的收入確認。

Of the $27.8 million, roughly $20 million related to the ongoing recognition of initial Sarepta consideration and $7 million related to reimbursement of collaboration-related costs. After the end of our third fiscal quarter, we announced two important events, each of which will have a positive impact on our financial position.

在這 2,780 萬美元中，約有 2,000 萬美元與 Sarepta 初始對價的持續確認有關，700 萬美元與合作相關費用的報銷有關。在第三財季結束後，我們宣布了兩件重要事件，每起事件都會對我們的財務狀況產生正面影響。

First, there is the $100 million DM1 milestone payment from Sarepta, which Chris mentioned earlier on the call. As this event occurred after June 30, revenue associated with this milestone will be recognized in our fiscal fourth-quarter financial results. We anticipate achieving the second DM1 development milestone valued at $200 million by the end of the calendar year.

首先，Sarepta 支付了 1 億美元的 DM1 里程碑付款，Chris 在先前的電話會議上提到。由於該事件發生在 6 月 30 日之後，與該里程碑相關的收入將在我們的第四季度財務業績中確認。我們預計在今年年底前實現價值 2 億美元的第二個 DM1 開發里程碑。

Second, on August 1, we announced that Sanofi signed an agreement to acquire exclusive rights to develop and commercialize investigational plozasiran in Greater China from Visirna Therapeutics, Arrowheads' majority-owned subsidiary.

第二，8月1日，我們宣布賽諾菲與Arrowheads的多數股權子公司Visirna Therapeutics簽署協議，獲得在大中華區開發和商業化試驗性藥物plozasiran的獨家權利。

Visirna will receive $130 million upfront on closing. Additionally, Visirna will receive up to $265 million in potential future regulatory milestone payments and potential royalties associated with the sales of plozasiran in Greater China.

Visirna 將在交易完成時獲得 1.3 億美元的預付款。此外，Visirna 還將獲得高達 2.65 億美元的潛在未來監管里程碑付款以及與大中華區 plozasiran 銷售相關的潛在特許權使用費。

We expect to record revenue of $130 million in the fourth quarter associated with the upfront payment only. Turning to expenses, total operating expenses for the quarter ended June 30, 2025, were $193.3 million compared to $176.1 million in the prior year quarter, or an increase of $17.2 million.

我們預計第四季僅與預付款相關的收入將達到 1.3 億美元。談到費用，截至 2025 年 6 月 30 日的季度總營運費用為 1.933 億美元，而去年同期為 1.761 億美元，增加了 1,720 萬美元。

The year-over-year increase was driven by, among other things, roughly $10 million of higher R&D costs, primarily as a result of our Phase 3 registrational trials for plozasiran in SHTG, as well as higher costs related to active candidates in the preclinical stage.

年比成長的原因包括約 1000 萬美元的研發成本增加，這主要是由於我們在 SHTG 進行的 plozasiran 第 3 階段註冊試驗，以及與臨床前階段的活躍候選藥物相關的成本增加。

It's worth bearing in mind that year-to-date, approximately 70% of our clinical trial spend can be attributed to the Phase 3 registrational trials for plozasiran in SHTG. As Bruce mentioned, these studies are now fully enrolled, and we expect data to read out next year.

值得記住的是，今年迄今為止，我們大約 70% 的臨床試驗支出可歸因於 SHTG 中 plozasiran 的 3 期註冊試驗。正如布魯斯所提到的，這些研究目前已全部入組，我們預計明年就能讀出數據。

Additionally, as planned, our SG&A costs have increased by $7 million year over year, driven primarily by our preparations for commercialization in advance of the FDA's upcoming PDUFA action date later this year on November 18.

此外，按照計劃，我們的銷售、一般及行政費用同比增加了 700 萬美元，這主要是因為我們要為今年晚些時候 11 月 18 日 FDA 即將頒布的 PDUFA 行動日期之前的商業化做好準備。

Turning to cash, net cash used in operating activities during fiscal quarter three 2025 was $154.7 million compared with net cash used in operating activities of $115.4 million in the prior year quarter. The increase in cash used in operating activities is driven by several factors, including the aforementioned higher operating expenses and timing of clinical trial payments.

談到現金，2025 財年第三季經營活動所用的淨現金為 1.547 億美元，而去年同期經營活動所用的淨現金為 1.154 億美元。經營活動所用現金的增加受到多種因素的影響，包括前面提到的更高的營運費用和臨床試驗付款的時間。

Turning to the balance sheet, our cash and investments totaled $900.4 million as of June 30, 2025. Our common shares outstanding as of the end of this quarter were 138.1 million.

談到資產負債表，截至 2025 年 6 月 30 日，我們的現金和投資總額為 9.004 億美元。截至本季末，我們流通在外的普通股為 1.381 億股。

And with that, I will now turn the call back over to Chris.

現在，我將把電話轉回給克里斯。

Thanks, Dan. Arrowhead continues to achieve strong execution in discovery, clinical, regulatory, and business development. Our pipeline has become increasingly mature, with four Arrowhead discovered candidates currently in pivotal Phase 3 studies. In addition, our commercial buildout is designed to make us launch ready very quickly, should plozasiran receive regulatory approval on the November 18, 2025, PDUFA date.

謝謝，丹。Arrowhead 在發現、臨床、監管和業務發展方面繼續取得強勁表現。我們的產品線已日益成熟，目前 Arrowhead 發現的四種候選藥物正處於關鍵的 3 期研究中。此外，如果 plozasiran 在 2025 年 11 月 18 日（PDUFA 日期）獲得監管部門批准，我們的商業建設將使我們能夠非常快速地做好上市準備。

And, lastly, we have a strong balance sheet that we think gives us the financial resources to continue to move multiple innovative new medicines through the clinical and regulatory process and ultimately get them to the patients who need them.

最後，我們擁有強大的資產負債表，我們認為這為我們提供了財務資源，可以繼續推動多種創新新藥通過臨床和監管流程，並最終將它們送到需要它們的患者手中。

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

感謝您今天加入我們，現在我想開始回答您的問題。

Thank you. At this time we'll conduct the question-and-answer session.(Operator Instructions)

謝謝。現在我們將進行問答環節。 （操作員指示）

Maury Raycroft, Jefferies

莫里‧雷克羅夫特（Maury Raycroft），傑富瑞

Good afternoon. This is Farzin on for Maury. So thank you for taking our question. When thinking about your own SHTG with ongoing successive three and four, how are you thinking about the prospects of competitor Ionis programs reading out in September from the core studies? Especially with respect to the triglyceride reduction as well as signals in the acute pancreatitis.

午安.這是法爾津 (Farzin) 代替莫里 (Maury) 上場的。感謝您回答我們的問題。當您考慮自己的 SHTG 正在進行的連續三期和四期專案時，您如何看待競爭對手 Ionis 計劃在 9 月從核心研究中得出的前景？特別是關於三酸甘油酯的降低以及急性胰臟炎的信號。

So I'll answer that. And then, Bruce, do you have anything that you think is necessary? Look, we can't we have no control over other people's studies. It's difficult to compare two drugs across two different studies Or more, frankly, in this respect. So we're just focused on our own studies here. You know, we've had very good data in our Phase 2 studies. We've had very good data in our Phase 3 study in FCS. And we think we've got a best-in-class triglyceride reducer here. We look forward to seeing what the FHTG data look like, but that is our expectation. We'll go from there. Bruce, do you have any data on that?

所以我會回答這個問題。那麼，布魯斯，您認為還有什麼是必要的嗎？看，我們無法控制別人的學習。坦白說，在這方面，很難在兩項不同的研究中比較兩種藥物。所以我們只專注於我們自己的研究。您知道，我們在第二階段的研究中獲得了非常好的數據。我們在 FCS 的第三階段研究中獲得了非常好的數據。我們認為我們已經擁有了一流的三酸甘油酯降低劑。我們期待看到 FHTG 數據是什麼樣子，但這是我們的期望。我們就從那裡出發。布魯斯，你有這方面的數據嗎？

Not really. As you said, you know, it's hard to compare across studies. I will say that, you know, what they have relayed about their patient population looks quite similar to our patient population at the time of enrollment. So I think it will be interesting for us to see what their data actually shows when they report it out in September and then probably in more detail at a later academic presentation.

並不真地。正如你所說，不同研究之間很難進行比較。我想說的是，他們所傳達的患者群體與我們入組時的患者群體非常相似。因此，我認為當他們在 9 月發布報告時，看看他們的數據實際上顯示了什麼將會很有趣，然後可能會在稍後的學術報告中更詳細地展示。

So we'll follow with interest, but yeah, how much bearing it has is always hard to tell.

因此我們會饒有興趣地關注，但是，是的，它到底有多大影響總是很難說。

And what is key here? In the studies and then once we are at market, our two primary things, I think. You know, one is how deeply can you reduce triglycerides from baseline? And second is how many patients can get to goal, whether that goal is defined as triglycerides below [880] or below [500], I think those are the key points here, and we expect physicians to look at that. We expect patients to look at that.

這裡的關鍵是什麼？在研究中，一旦我們進入市場，我認為我們要做兩件主要的事情。你知道，一個問題是你能將三酸甘油酯從基線降低到什麼程度？其次，有多少患者能夠達到目標，無論該目標定義為三酸甘油酯低於 [880] 或低於 [500]，我認為這些是關鍵點，我們希望醫生關注這一點。我們希望患者能夠看到這一點。

Got it. Thank you.

知道了。謝謝。

Right. Thank you.

正確的。謝謝。

Jason Gerberry, Bank of America.

美國銀行的 Jason Gerberry。

Hey, guys. Thanks for taking my questions. So another question on the SHTG program. If I heard you right, so it sounds like what you're confirming is your baseline demographics of your two phase three studies look similar to the published baseline demographics that Ionis had published for its core studies. I guess that would be in terms of the two key subgroups, which is ultra-high triglyceride levels and past history of AP. And I'm curious your thoughts. Ionis indicated that they are seeing events on a blinded basis, at least 13. With, like, a skew of, like, 700 drug, 300 placebo, something like that.

嘿，大家好。感謝您回答我的問題。關於 SHTG 計劃還有另一個問題。如果我沒聽錯的話，聽起來您要確認的是，您的兩個第三階段研究的基線人口統計數據與 Ionis 為其核心研究發布的基線人口統計數據相似。我猜想這將涉及兩個關鍵亞組，即超高甘油三酯水平和 AP 既往病史。我很好奇你的想法。伊奧尼斯表示，他們正在盲目觀察至少 13 起事件。例如，有 700 種藥物，300 種安慰劑，諸如此類。

So just kind of curious as you absorb that because, like, the event rate's the big unknown here. I'm just kind of curious, you know, has your thoughts changed at all around the probability of showing at least a strong numerical trend by pooling the SHASTA-4, 5 studies. Thanks.

所以當你吸收這一點時，你只是有點好奇，因為事件發生率是這裡最大的未知數。我只是有點好奇，你知道，透過匯總 SHASTA-4、5 研究，你對至少顯示出強勁數值趨勢的機率的想法是否發生了改變。謝謝。

I think that's an it's difficult to answer that question Jason. And the reason is because we count true adjudicated cases of pancreatitis. The Ionis approach is not just counting pancreatitis, but also abdominal pain. And, of course, abdominal pain can be nonspecific. Although the effort is to determine that abdominal pain when it occurs is actually not related to other elements such as alcohol or gallstones, for instance. But it is a little bit of an apples-to-oranges comparison of actual pancreatitis to abdominal pain events.

我認為這個問題很難回答，傑森。原因是我們統計了真正的胰臟炎裁定病例。Ionis 方法不僅計算胰臟炎，也計算腹痛。當然，腹痛也可能不是特異性的。儘管努力是為了確定腹痛發生時實際上與酒精或膽結石等其他因素無關。但這有點像是將實際的胰臟炎與腹痛事件進行蘋果和橘子的比較。

So it's hard to know what they're going to show in the end regarding pancreatitis, which I think is the most important measure. Abdominal pain matters in SHTG and high triglycerides. It can be debilitating for patients and difficult, but it's not a fatal thing, where pancreatitis produces organ damage and can lead to fatality.

因此很難知道他們最終會對胰臟炎做出何種診斷，但我認為這是最重要的指標。腹痛與 SHTG 和高三酸甘油酯有關。它會使患者虛弱且困難，但這並不是致命的，而胰臟炎會造成器官損害並導致死亡。

So it's a much different, it's a much different animal for physicians to manage and, of course, for payers to deal with as well. So that part of it is harder to assess, and I'm not sure that we'll get granularity on that, even when they announce their results in September. So it's a little bit difficult to say, Jason, at this time. We will track abdominal pain as well, but we're really focused on acute pancreatitis given that's the real disease with severity.

所以，對於醫生來說，這是一個非常不同的事情，對於付款人來說，當然也是一個非常不同的事情。因此，這部分內容更難評估，而且我不確定我們是否能獲得詳細的信息，即使他們在九月公佈結果。所以傑森，現在有點難說。我們也會追蹤腹痛，但我們真正關注的是急性胰臟炎，因為這才是真正嚴重的疾病。

And will you guys be publishing your baseline demographics, I don't know, in the next six to nine months or so?

你們會在未來六到九個月左右發布基線人口統計嗎？我不知道。

Yes. I think we will. We'll be submitting that, you know, for future medical conferences for sure.

是的。我想我們會的。您知道，我們肯定會將其提交給未來的醫學會議。

Okay, thank you.

好的，謝謝。

You bet.

當然。

David Lebowitz, Citi.

花旗銀行的 David Lebowitz。

Hi there. This is Mary Kate on for David today. Thanks so much for your overview of the anticipated FCS launch. I guess, how does this treatment address the clinical unmet need in this space, and maybe what feedback are you receiving from physicians ahead of this potential launch? Thank you.

你好呀。今天是瑪麗凱特 (Mary Kate) 為大衛主持節目。非常感謝您對預期的 FCS 發布的概述。我想問，這種治療方法如何解決該領域未滿足的臨床需求？在這種治療方法可能推出之前，您從醫生那裡得到了什麼回饋？謝謝。

Andy, you take that, and Bruce, add anything that you think should be added.

安迪，你拿著這個，布魯斯，添加你認為應該添加的任何內容。

Yeah. Happy to take that. So thank you for the question, Mary Kate, related to the clinical unmet need. What we know with respect to familial chylomicronemia syndrome patients is that they suffer from physical symptoms, including abdominal pain and, of course, as Bruce mentioned, acute pancreatitis, which can lead to recurrent pancreatitis, necrotizing pancreatitis, and in some instances, fatality.

是的。很高興接受這個。瑪麗凱特，謝謝你提出有關臨床未滿足需求的問題。就家族性乳糜微粒血症症候群患者而言，我們知道他們會出現身體症狀，包括腹痛，當然，正如布魯斯所提到的，還有急性胰臟炎，這可能導致復發性胰臟炎、壞死性胰臟炎，在某些情況下甚至會導致死亡。

And so one of the big things that we believe plozasiran addresses as far as meeting the unmet need, first and foremost, is the deep reduction of triglycerides to levels that have never been seen before with existing therapies in this space. We've talked about an 80% reduction from baseline seen in the PALISADE study.

因此，我們認為，就滿足未滿足的需求而言，plozasiran 所解決的首要問題之一就是將三酸甘油酯大幅降低至現有療法從未達到的水平。我們已經討論過 PALISADE 研究中看到的相對於基線的 80% 的減少。

But moreover, the outcome of interest, of course, is the reduction in acute pancreatitis risk, and plozasiran is the only agent in a registrational Phase 3 study that has demonstrated a statistically significant reduction in acute pancreatitis risk in PALISADE. So those are two of the primary unmet needs that we believe plozasiran can address in FCS. I would say moreover, just from a patient convenience and tolerability perspective, plozasiran does continue to have a very desirable profile with only quarterly, so four injections a year, which is very different than the current treatment regimens that are available for these patients presently. So hopefully that addresses your question around why we believe plozasiran fills some important unmet clinical needs.

但此外，感興趣的結果當然是降低急性胰臟炎風險，而 plozasiran 是註冊 3 期研究中唯一證明在 PALISADE 中顯著降低急性胰臟炎風險的藥物。因此，我們認為 plozasiran 可以解決 FCS 中的兩個主要未滿足需求。此外，我想說，僅從患者的便利性和耐受性角度來看，plozasiran 確實仍然具有非常理想的效果，只需每季注射一次，即每年註射四次，這與目前這些患者可用的治療方案非常不同。所以希望這能回答您的問題，為什麼我們相信 plozasiran 可以滿足一些重要的未滿足的臨床需求。

Patrick Trucchio, H. C. Wainwright.

派崔克‧特魯基奧、H.C. 溫賴特。

Thanks. Good afternoon, and congrats on all the progress. I'm just wondering, as payer access appears favorable for both genetically confirmed and clinically defined FCS, is there any differentiation in the coverage path for high-risk, severe high triglyceride patients, particularly those that don't have a pancreatitis history?

謝謝。下午好，祝賀你取得的所有進展。我只是想知道，由於付款人訪問似乎對基因確診和臨床定義的 FCS 都有利，那麼對於高風險、嚴重高三酸甘油酯患者，特別是那些沒有胰臟炎病史的患者，覆蓋路徑是否有任何區別？

And I guess I'm just wondering if you can speak to your expectations for pricing between FCS and severe high triglyceride indications, particularly just given the different population sizes and medical cost burden?

我只是想知道您是否可以談談您對 FCS 和嚴重高三酸甘油酯適應症之間的定價預期，特別是考慮到不同的人口規模和醫療成本負擔？

So regarding pricing, we are not prepared to opine too much on a potential SHTG price. We are still looking into that. We certainly would expect that to be a lower-priced drug than FCS. But beyond that we're still working on that question.

因此，關於定價，我們不準備對潛在的 SHTG 價格發表太多意見。我們仍在調查此事。我們當然希望這是一種比 FCS 價格更低的藥物。但除此之外，我們仍在努力解決這個問題。

Prakhar Agarwal, Cantor.

普拉卡爾·阿加瓦爾 (Prakhar Agarwal)，領唱。

Hi. Congrats on the quarter and thank you for taking my questions. So maybe on the Sarepta situation, I think Sarepta also owns 10 million plus shares of Arrowhead Pharmaceuticals stock. So what could be a practical solution here to solve for this if Sarepta intends to sell their shares?

你好。恭喜本季取得佳績，感謝您回答我的問題。因此，就 Sarepta 的情況而言，我認為 Sarepta 還擁有 1,000 多萬股 Arrowhead Pharmaceuticals 股票。那麼，如果 Sarepta 打算出售其股份，那麼解決這個問題的實際可行的方案是什麼？

And secondly, on SHTG, maybe a question for Andy. What sort of commercial activities are you doing to educate the community about how SHTG is different from the lipid market? It seems that the street has been anchored to lipid pricing and the update there for the drugs. Any color there would be helpful. Thank you.

其次，關於 SHTG，我想問安迪。您正在進行哪些商業活動來讓社區了解 SHTG 與脂質市場有何不同？看來這條街已經錨定了脂質定價和藥品的更新。任何顏色都會有幫助。謝謝。

Sure. Yes, Sarepta does own some Arrowhead Pharmaceuticals shares. Their lockup period is still in effect right now. I don't know, I can't tell you what their plan is for those shares. I can tell you that we have had inbound interest in acquiring shares, and so I'm not so worried that if they decide to sell those, that they can find a buyer. They certainly could. But I don't know what the longer-term plans are in terms of holding on to those shares and for how long. Andy, you want to address the education?

當然。是的，Sarepta 確實擁有一些 Arrowhead Pharmaceuticals 的股份。他們的鎖定期目前仍然有效。我不知道，我無法告訴你他們對這些股票的計畫是什麼。我可以告訴你，我們一直有興趣收購股票，所以我並不擔心如果他們決定出售這些股票，他們能否找到買家。他們當然可以。但我不知道持有這些股票的長期計劃是什麼以及持有多長時間。安迪，你想談談教育議題嗎？

Yeah. Thanks, Prakhar. As it relates to education, of course, we have active medical education in the form of our medical science liaisons who are conducting scientific exchange. Moreover, there is independent medical education, continued medical education that's ongoing related to individuals with extremely high triglycerides, the unmet medical need, burden of disease, and education around clinical study results.

是的。謝謝，普拉卡爾。當然，就教育而言，我們透過醫學科學聯絡員進行科學交流，積極進行醫學教育。此外，還有獨立的醫學教育、與三酸甘油酯極高的個人、未滿足的醫療需求、疾病負擔以及圍繞臨床研究結果的教育相關的持續醫學教育。

Certainly, in the case of Palisade, I would say a lot of the education that's happening now in the community is related to education around the disease burden, around goal attainment, namely an education around the guideline-directed risk threshold of 500 milligrams per deciliter, and then, of course, the focus on the outcome of interest, which is acute pancreatitis events.

當然，就 Palisade 的情況而言，我想說，目前社區中開展的許多教育都與疾病負擔、目標實現有關，即圍繞指南指導的風險閾值 500 毫克/分升的教育，當然，重點關注感興趣的結果，即急性胰臟炎事件。

And so that largely is the focus of our education. And as our commercial field team gets out into the field towards the end of this month, of course, they will be highly focused on similar disease education as well. I hope that answers your question.

所以這在很大程度上就是我們教育的重點。當然，當我們的商業現場團隊在本月底進入現場時，他們也會高度關注類似的疾病教育。我希望這能回答你的問題。

And your question is in this do one. Yes triglycerides can be found on the standard lipid panel. But when people think about lipid drugs, they generally think about them in the context of ASCVD. This is not what this drug is. Plozasiran is not an ASCVD drug. (technical difficulty) Plozasiran is a pancreatitis drug, and I think should be thought of as such. And priced as such, to be honest. You know? So they so yes, it is this is a limited parameter, but it is not an ASCVD drug. This is a pancreatitis drug. And there are populations that are at substantial risk of pancreatitis, acute pancreatitis, with the high levels of triglycerides.

而你的問題就在這個裡面。是的，可以在標準脂質面板上找到三酸甘油酯。但當人們考慮脂質藥物時，他們通常會在 ASCVD 的背景下考慮它們。這不是這種藥物的本質。Plozasiran 不是 ASCVD 藥物。（技術難題）Plozasiran是一種胰臟炎藥物，我認為應該這樣看待。說實話，價格也是。你知道？所以是的，這是一個有限的參數，但它不是 ASCVD 藥物。這是一種治療胰臟炎的藥物。有些人體內三酸甘油酯水平較高，罹患胰臟炎（急性胰臟炎）的風險很大。

So I think that's the way you need to look at it.

所以我認為這就是你需要看待它的方式。

Eliana Merrill, UBS

瑞銀集團（UBS）的 Eliana Merrill

Hi. This is Joseph on for Eliana. Thank you for taking my question, and congrats on initiating the Yosemite trial for zodasiran. I'm wondering if you can talk about your latest on your estimations of the size of the HoFH addressable patient population. Thank you.

你好。這是 Joseph 為 Eliana 表演的。感謝您回答我的問題，並祝賀您啟動 zodasiran 的 Yosemite 試驗。我想知道您是否可以談談您對 HoFH 可治療患者群體規模的最新估計。謝謝。

Anthony, you're probably the expert on that. Why don't you take that one?

安東尼，你可能是這方面的專家。為什麼不拿那個呢？

Yeah. So the literature would suggest the prevalence for HoFH is anywhere from roughly one in five hundred thousand to one in 1 million persons. And so there's been quite a lot of evidence produced in the HoFH space over the years as new therapies have become available. So we see the accessible population for being similar to those estimates

是的。因此，文獻表明，HoFH 的盛行率大約為五十萬分之一到百萬分之一。隨著新療法的出現，多年來在 HoFH 領域產生了相當多的證據。因此，我們看到可訪問的人口與這些估計值相似

Edward Tenthoff, Piper Sandler.

愛德華·坦托夫、派珀·桑德勒。

Great. Thank you very much. Actually, a little housekeeping question, if I may. Congrats on the Vicerna deal. So does that cash go to Arrowhead Pharmaceuticals, and is it able for you guys to invest that? (technical difficulty)

偉大的。非常感謝。實際上，如果可以的話，我想問一個小問題。祝賀與 Vicerna 達成交易。那麼這些錢會流向 Arrowhead Pharmaceuticals 嗎？你們可以投資這些錢嗎？（技術難度）

So the cash goes into Viscera. And a portion of that, a large portion of that, will be distributed to shareholders of Viscernet, and as I mentioned in the prepared remarks, at close, we'll have about 56% of Viscernia.

因此現金進入了 Viscera。其中很大一部分將分配給 Viscernet 的股東，正如我在準備好的演講中提到的那樣，在收盤時，我們將擁有 Viscernet 約 56% 的股份。

Not all will go out. There will be some tax liabilities, and also, you need to leave some cash in the company because, as I mentioned, they also have ongoing studies with plozasiran related to FHTG, although, again, we will take that over. They also have studies with zodasiran. They also have some ARO HSD studies ongoing. It's not a huge cost, but there is some cost there.

並非所有人都會出去。會有一些稅務責任，而且，你需要在公司留下一些現金，因為正如我所提到的，他們還在進行與 FHTG 相關的 plozasiran 研究，儘管，我們會再次接手這些研究。他們也對 zodasiran 進行了研究。他們也正在進行一些 ARO HSD 研究。雖然這不是什麼大成本，但還是需要一些成本。

Ultimately, again, as I mentioned in the prepared remarks, my goal here is to monetize the China rights for zodasiran and the China rights for ARO HSD in a similar manner that we did for plozasiran. So, anyway, long story short is, you know, we will bring home, I think, a substantial amount of that capital, but not all of it.

最終，正如我在準備好的發言中提到的那樣，我的目標是將 zodasiran 的中國權利和 ARO HSD 的中國權利貨幣化，就像我們對 plozasiran 所做的那樣。所以，總之，長話短說，你知道，我認為我們將帶回相當一部分資本，但不是全部。

Great. That's helpful. And then when it comes to the R&D, the annual R&D from Sarepta, is that paid all at once on the annual anniversary thing? Thanks.

偉大的。這很有幫助。那麼，說到研發，Sarepta 的年度研發費用是在週年紀念日一次性支付的嗎？謝謝。

Yeah. So they will pay us $50 million a year over five years. That payment is due in the first quarter of every year. So I believe it's February. Is that right, Dan? I mean, it's February. And so we have $100 million due now for the first DM1 milestone, $200 million that we think we'll trigger at the end of the year, and then a further $50 million due for the annual payments in February.

是的。因此，他們將在五年內每年向我們支付 5000 萬美元。該款項應於每年第一季支付。所以我相信是二月。是這樣的嗎，丹？我的意思是，現在是二月。因此，我們現在需要支付 1 億美元作為第一個 DM1 里程碑，2 億美元我們認為我們將在年底觸發，然後還需要支付 5000 萬美元作為 2 月份的年度付款。

Great. Thanks guys.

偉大的。謝謝大家。

You're welcome. Thank you.

不客氣。謝謝。

Luca Issy, RBC Capital Markets.

加拿大皇家銀行資本市場 (RBC Capital Markets) 的 Luca Issy。

Great, thanks guys for taking the question. This is Shelby on for Luca. Can you just talk about the initial presentation for plozasiran? Our understanding is that initial approval will be for prefilled syringes. So is that correct? And if so, what is the path to have it in the form of an auto-injector, and how should we think about that timeline? Thanks.

太好了，謝謝大家回答這個問題。這是謝爾比 (Shelby) 為盧卡 (Luca) 表演的。能談談 plozasiran 的初步介紹嗎？我們的理解是，初步批准的是預充式註射器。那麼這是正確的嗎？如果是這樣，那麼以自動注射器的形式實現它的途徑是什麼，我們應該如何考慮這個時間表？謝謝。

Sure. Andy, you want to discuss that, and then Bruce, want to talk about more of the granularity of the auto-injector

當然。安迪，你想討論這個問題，然後布魯斯，想談談自動注射器的更多細節

Yeah. That's right, Shelby. So our initial presentation for plozasiran in the FCS space will be a prefilled syringe. And there is development underway for an auto-injector in the SHTG space. Bruce, if you want to comment anymore on that.

是的。沒錯，謝爾比。因此，我們在 FCS 領域首次展示的 plozasiran 將是一種預充式註射器。目前，SHTG 領域的自動注射器的開發正在進行中。布魯斯，如果你想對此進一步發表評論。

Yeah. I would just say that the auto-injector will be either available at the time of launch for the SHTG indication or soon thereafter. That's our current expectation.

是的。我只想說，自動注射器將在 SHTG 指示發佈時或發布後不久推出。這是我們目前的期望。

Great. Thanks.

偉大的。謝謝。

Mani Foroohar, Leerink.

Mani Foroohar，Leerink。

Hi, guys. Have Ryan on for Mani. Congrats on the quarter. Maybe shifting over to the INHBE readout later this year, can you just share a little detail around which cohorts we should expect to see data from, whether that's the SAD, MAD, combo, and then internally, what are you guys really hoping to see here relative to the other data sets from muscle-sparing agents that we've seen so far? Thanks.

嗨，大家好。讓 Ryan 代替 Mani。恭喜本季取得佳績。也許今年晚些時候會轉到 INHBE 讀數，您能否分享一些細節，關於我們應該期望看到哪些隊列的數據，無論是 SAD、MAD 還是組合，然後在內部，相對於我們迄今為止看到的其他肌肉保留劑的數據集，你們真正希望在這裡看到什麼？謝謝。

Yeah, sure. I can take that. We'll have data from all of those cohorts that you mentioned, SAD, MAD, as well as the combination cohorts, and we'll be measuring a handful of different biomarkers, including PDE biomarkers, like measurable activity in the blood. Of course, we can look at body composition based on MRI and weight loss changes in body weight. Then, of course, we've got a whole host of lipid parameters and glycemic control parameters that we'll look at.

是的，當然。我可以接受。我們將獲得您提到的所有隊列的數據，包括 SAD、MAD 以及組合隊列，並且我們將測量一些不同的生物標記物，包括 PDE 生物標記物，例如血液中可測量的活動。當然，我們可以根據MRI和體重減輕的變化來觀察身體組成。當然，我們會得到大量的脂質參數和血糖控制參數供我們研究。

Mike Ulz, Morgan Stanley

摩根士丹利的麥克烏爾茲

Good afternoon, and thanks for taking the question. Maybe just a follow-up on the last question related to the obesity updates later this year. Just curious if you see what you want to see there, what would be some of the scenarios around next steps for those programs? Thanks.

下午好，感謝您回答這個問題。也許只是今年稍後肥胖更新相關的最後一個問題的後續回答。只是好奇，如果您看到了您想看到的內容，那麼這些程序的下一步計劃會是什麼樣的？謝謝。

Yeah. So those are hard questions. I don't think we go into most studies with an idea that if we see X, we will move forward in some manner. If we see Y, we will move forward in some other manner, if we see Z, we won't move forward. You know, we're in the truth-seeking business. We will do the study, and we'll see what the data look like, and then move on from there. But I don't mean to evade your question. We just don't go into these studies with any sort of preconceived ideas about what might come next until we see some data.

是的。所以這些都是很難的問題。我認為，我們在進行大多數研究時並不認為如果我們看到了 X，我們就會以某種方式向前發展。如果我們看到 Y，我們就會以其他方式前進，如果我們看到 Z，我們就不會前進。你知道，我們從事的是尋求真相的事業。我們將進行研究，看看數據是什麼樣的，然後繼續前進。但我無意迴避你的問題。在看到一些數據之前，我們不會帶著任何關於接下來會發生什麼的先入為主的想法來進行這些研究。

Understood. Thank you.

明白了。謝謝。

Thank you. Yeah, I just would just sort of add to that we need to keep in mind that these are novel mechanisms. These are not just another GLP-1 agonist access sort of drug where we're looking at different behaviors and really looking for white space opportunities here. And it's very hard to predict those. It's much easier to answer a question like that if you're coming in with the tenth GLP-1 agonist. But it's quite hard to answer that question when you're dealing with a completely novel mechanism that has not been in humans before.

謝謝。是的，我只是想補充一點，我們要記住這些都是新穎的機制。這些不僅僅是另一種 GLP-1 激動劑類藥物，我們正在研究它們的不同行為並真正尋找這裡的空白機會。這些都很難預測。如果您了解第十種 GLP-1 激動劑，那麼回答這樣的問題就容易得多。但是當你面對一種以前從未在人類身上出現過的全新機制時，要回答這個問題就相當困難了。

Makes sense, thank you.

有道理，謝謝。

Joseph Thome, TD Cowen

約瑟夫·托米（Joseph Thome），考恩（Cowen）TD

Hi, there. Good afternoon, and thank you for taking my question. Maybe on the MUIR 3 study, I guess, given that these patients will likely have a lower mean fasting triglyceride level, is there an increased risk that potentially this patient subset would be more at risk to self-adherence of, or self-liberalization of diet or maybe a little bit of a less adherence to background lipid-lowering therapy than you might see in SHASTA-3, 4. And, I guess, could that create some variability in the AE profile or endpoints? I guess why or why not?

你好呀。下午好，感謝您回答我的問題。我猜，在 MUIR 3 研究中，考慮到這些患者的平均空腹三酸甘油酯水平可能較低，與 SHASTA-3、4 中看到的情況相比，這部分患者自我堅持或自我放寬飲食習慣的風險是否會更高，或者對背景降脂療法的依從性可能會略低一些。而且，我猜，這會在 AE 設定檔或端點中產生一些變化嗎？我猜為什麼或為什麼不？

And then when you think about the readouts for these three trials, would these all come at the same time and it would be one top-line release, or would these be discrete events? Thank you.

然後，當您考慮這三個試驗的讀數時，它們是否會同時出現並成為一個頂線發布，還是它們是離散事件？謝謝。

So taking that first question look in clinical trials, we do our best to try to encourage participants to follow the protocol. We give them frequent dieting advice and reminders. And it's hard to estimate whether they're going to behave all that differently than the SHTG. I would say that we did two trials in mixed hyperlipidemia in the last few years, one with plozasiran, one with zodasiran, and I wouldn't say that the behavior in those trials was all that different than we saw at SHASTA-2 or PALISADE with respect to adherence to the protocol. It was pretty good for both.

因此，在臨床試驗中，首先要考慮的問題是，我們盡力鼓勵參與者遵守方案。我們經常給他們節食建議和提醒。而且很難估計他們的行為是否會與 SHTG 有太大不同。我想說的是，我們在過去幾年中對混合性高脂血症進行了兩項試驗，一項使用了 plozasiran，一項使用了 zodasiran，而且我不會說這些試驗中的行為與我們在 SHASTA-2 或 PALISADE 中看到的在遵守方案方面的行為有什麼不同。這對雙方來說都很好。

Now that may be partly because we pay a lot of attention to the detail of execution of clinical trials, and we tend to have a low dropout rate and a pretty good adherence rate, probably in no small part because of that. But I'm not too concerned about that. And, of course, we have placebos in these trials, and you expect the placebo behavior to sort of mimic the behavior that you get in the active treatment arms. So, hopefully, whatever you see balances out anyway relative to placebo. But I don't think we're expecting anything particularly different.

這可能部分是因為我們非常注重臨床試驗執行的細節，而且我們的退出率往往很低，而且依從率也相當高，這可能在很大程度上是因為這一點。但我對此並不太擔心。當然，我們在這些試驗中使用了安慰劑，你希望安慰劑行為能模仿你在積極治療組中所得到的行為。因此，希望您所看到的一切與安慰劑相比都是平衡的。但我不認為我們期待任何特別不同的事情。

Great, thank you. And then the last part was, are these going to read out at the same time in top line, or will these be three separate releases?

太好了，謝謝。最後一部分是，這些內容會同時在第一行讀出嗎，還是會分成三個單獨的版本？

I don't think we've really come to a determination on that. In theory, we'll have the data from these trials fairly close together, but I don't think they will all show up on the same day. So I'll leave it to Chris if he wants to predict how we'll make that decision a year from now.

我認為我們還沒有真正就此做出決定。理論上，我們會得到這些試驗相當接近的數據，但我認為它們不會在同一天全部出現。因此，如果克里斯想預測我們一年後會如何做出決定，我會讓他來決定。

Yeah. My thinking, my first thought on that is that it's yes. They are three separate studies, but they're part of one [grander] study, and so it would seem to make sense to release them all at once. But we haven't really discussed that.

是的。我的想法，我對此的第一個想法是肯定的。它們是三項獨立的研究，但它們是一項（更大）研究的一部分，因此一次性發布它們似乎是有意義的。但我們還沒有真正討論過這個問題。

Perfect. Thank you very much again.

完美的。再次感謝您。

Thank you. William Pickering, Bernstein.

謝謝。威廉‧皮克林，伯恩斯坦。

Hey guys, congrats on the progress and thank you for taking my question. It's about your DM1 program. At your muscle R&D day last year, you indicated you were planning to dose up to 12 MPK in that initial study. My understanding is the highest dose under the current protocol is 6 MPK, and that's unchanged from when Sarepta licensed the product last November. Is my understanding correct? And if so, what was the Rationale for reducing that max dose versus the prior plan and for having a lower max dose than the FSHD study. Thank you.

嘿，大家好，祝賀你們取得進展，感謝你們回答我的問題。這是關於您的 DM1 程式的。在去年的肌肉研發日上，您表示計劃在初步研究中劑量高達 12 MPK。我的理解是，目前方案下的最高劑量是 6 MPK，這與去年 11 月 Sarepta 授權產品時相比沒有變化。我的理解正確嗎？如果是這樣，那麼與先前的計劃相比減少最大劑量以及與 FSHD 研究相比最大劑量更低的理由是什麼。謝謝。

It should, so we still can go up to 12 (inaudible) per gig in the current study, the DM1 study.

應該如此，因此在目前研究（DM1 研究）中，我們仍然可以將每場演出提高到 12（聽不清楚）。

Thank you. Madison El-Saadi, B. Riley.

謝謝。麥迪遜·埃爾薩迪、B. 萊利。

Hey guys, congrats on the quarter. Thanks for taking our question. I guess maybe going back to obesity, given that the in size, the sample size, I guess, is it your assumption that any statistical conclusions are achievable, or is that kind of precluded here and just assuming a competitive muscle sparing weight loss, is it achieved? Where do you think you need to land on a frequency of dosing to be competitive, given there are other muscle sparing, candidates being developed, including other siRNA candidates?

嘿夥計們，恭喜本季。感謝您回答我們的問題。我想也許回到肥胖問題，考慮到樣本量的大小，我想，您是否假設任何統計結論都是可以得出的，或者在這裡是否排除了這一點，而只是假設一種競爭性的肌肉保留減肥，是否實現了？考慮到還有其他肌肉保護候選藥物（包括其他 siRNA 候選藥物）正在開發中，您認為需要將給藥頻率定在什麼水平才能保持競爭力？

Thanks. Sure, so this phase one study is really hypothesis generating. There's not that empowering necessarily that goes in the cohort size. I think the effect size that we will see from this study would be used to power a subsequent study down the road. And then in terms of frequency, we're looking at the most frequent, probably quarterly dose administration.

謝謝。當然，所以第一階段的研究其實只是產生假設。群體規模並不一定意味著賦權。我認為我們從這項研究中看到的效果大小將用於推動後續研究。然後就頻率而言，我們正在研究最頻繁的劑量管理，可能是每季一次。

So I'm not sure if there's anything out there that can match that frequency to date, and certainly not the (inaudible) at least not that I've seen, and some of the muscles sparing molecules are probably more frequent than that.

因此，我不確定是否有任何東西可以匹配迄今為止的頻率，當然不是（聽不清楚）至少我沒有見過，並且一些肌肉保護分子可能比這更頻繁。

So, we're looking at quarterly to every six months. Beyond that, I don't really see any benefit to even less frequent dosing. So I think we're in a pretty good place in terms of frequency of dose administration at quarterly dosing.

因此，我們考慮每季到每六個月進行一次。除此之外，我真的看不出減少服藥頻率有什麼好處。因此我認為我們在每季給藥的劑量管理頻率方面處於相當不錯的水平。

Got it. That's very helpful. Thanks.

知道了。這非常有幫助。謝謝。

Thank you. Morgan Lambarti, Goldman Sachs.

謝謝。高盛的摩根·蘭巴蒂。

Hi, thank you for taking a question. This is Morgan on for [Andrea Newkirk], kind of going back. Obesity, and specifically ALK7, can you speak more to how you're delivering sIRNA to adipocytes and then recognizing that it has not been explored in humans? What gives you confidence in the safety profile? What potential risks could you see in this targeting and is there a good loss of function data out there for us to see? Thank you.

您好，感謝您回答問題。這是摩根 (Morgan) 代替 [安德里亞紐柯克 (Andrea Newkirk)] 上場的表演，有點像是回去了。肥胖，特別是 ALK7，您能否詳細談談如何將 sIRNA 遞送至脂肪細胞，然後認識到它尚未在人類身上進行探索？什麼讓您對安全性有信心？您認為此次目標定位有哪些潛在風險？是否有充足的功能喪失數據可供我們查看？謝謝。

Sure. Yeah, see if we can hit all of those maybe in reverse order. So there are data on loss of function ALK7, in the loss of function carriers, we know there are at least a few homozygous walking around that seem to not have any issues.

當然。是的，看看我們是否可以以相反的順序完成所有這些。因此，有關於 ALK7 功能喪失的數據，在功能喪失的攜帶者中，我們知道至少有少數純合子似乎沒有任何問題。

Then, of course, there's a lot of heterozygous ALK7 loss of function carriers that seem otherwise phenotypically normal. They can be protected from things like type 2 diabetes and have an improved body composition, improved BMI-adjusted waist-to-hip ratio. The molecule itself does use a ligand-targeted approach that's selected for adipose tissues, adipocytes. So there is a ligand-driven approach that's facilitating uptake of the siRNA into the cell.

當然，有很多雜合的 ALK7 功能喪失攜帶者在表型上看起來是正常的。他們可以免受 2 型糖尿病等疾病的困擾，並改善身體成分，改善 BMI 調整後的腰臀比。該分子本身確實使用針對脂肪組織、脂肪細胞選擇的配體標靶方法。因此，存在一種配體驅動的方法，可以促進 siRNA 進入細胞。

And then beyond the human genetic data, what gives us confidence from a safety standpoint to start the study is, of course, all the non-GLP and GLP [tox] studies that we've done in nonhuman primates and in rodent species, and of course, in those, we go up to doses about many multiples of the doses we plan to use in the clinical trial. And those were all completed without any dose-limiting tox. And so I think we're in a pretty good position as far as safety goes going into this Phase 1 study.

除了人類基因數據之外，從安全角度來看，讓我們有信心開始研究的當然是我們在非人類靈長類動物和囓齒動物中進行的所有非 GLP 和 GLP [毒性] 研究，當然，在這些研究中，我們採用的劑量是我們計劃在臨床試驗中使用的劑量的許多倍。並且所有這些都是在沒有任何劑量限制毒性的情況下完成的。因此我認為，就第一階段研究的安全性而言，我們處於相當有利的地位。

Awesome. Thank you so much.

驚人的。太感謝了。

Thank you. This concludes the question-and-answer session. I would now like to turn it to Chris Anzalone, CEO, for closing remarks.

謝謝。問答環節到此結束。現在我想請執行長 Chris Anzalone 致最後總結。

Thank you all for joining us today, and I wish you all a good end of the summer, and we will see you next quarter.

感謝大家今天加入我們，祝大家夏天有個愉快的結束，我們下個季度再見。

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

感謝大家參加今天的會議。該計劃確實就此結束。您現在可以斷開連線。