Alnylam Pharmaceuticals Inc (ALNY) 2025 Q3 法說會逐字稿

Good morning, ladies and gentlemen, and welcome to the Alnylam Pharmaceuticals 3Q 2025 earnings conference call. (Operator Instructions) Also note that this call is being recorded on Thursday, October 30, 2025.

女士們、先生們，早安，歡迎參加 Alnylam Pharmaceuticals 2025 年第三季財報電話會議。（操作員指示）另請注意，本次通話將於 2025 年 10 月 30 日星期四進行錄音。

And now I would like to turn the conference over to management. Please go ahead.

現在我想把會議交給管理階層。請繼續。

Good morning. I'm Christine Akinc, Chief Corporate Communications Officer at Alnylam. With me today are Yvonne Greenstreet, Chief Executive Officer; Tolga Tanguler, Chief Commercial Officer; Pushkal Garg, Chief Research and Development Officer; and Jeff Poulton, Chief Financial Officer.

早安.我是克莉絲汀‧阿金克，Alnylam公司的首席企業傳播長。今天與我一同出席的有：執行長伊馮娜·格林斯特里特；首席商務官托爾加·坦古勒；首席研發官普什卡爾·加格；以及首席財務官傑夫·波爾頓。

For those of you participating via conference call, the accompanying slides can be accessed by going to the Events section of the Investors page of our website, investors.alnylam.com/events. During today's call, as outlined on slide 2, Yvonne will offer some introductory remarks and provide general context.

如果您是透過電話會議參與的，可以透過造訪我們網站投資者關係頁面的「活動」部分（investors.alnylam.com/events）查看相關投影片。在今天的電話會議中，如幻燈片2所示，Yvonne將作開場白並提供一些背景資訊。

To will provide an update on our global commercial progress. Pushkal will review pipeline updates and clinical progress, and Jeff will review our financials and guidance, followed by a summary of upcoming milestones before we open the call to your questions.

我們將向大家報告我們的全球商業進展。Pushkal 將回顧產品線更新和臨床進展，Jeff 將回顧我們的財務狀況和業績指引，隨後概述即將到來的里程碑，之後我們將開放電話會議回答您的問題。

I would like to remind you that this call will contain remarks concerning Alnylam's future expectations, plans and prospects, which constitute forward-looking statements for the purpose of the safe harbor provision under the Private Securities Ligation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in our most recent periodic report on file with the SEC.

我想提醒各位，本次電話會議將包含有關 Alnylam 未來預期、計劃和前景的評論，這些評論構成 1995 年《私人證券訴訟改革法案》安全港條款所指的前瞻性陳述。由於各種重要因素的影響，實際結果可能與這些前瞻性聲明所指出的結果有重大差異，這些因素包括我們在最近向美國證券交易委員會提交的定期報告中討論的因素。

In addition, any forward-looking statements represent our views only as of the date of this recording and should not be relied upon as representing our views of any subsequent date. We specifically disclaim any obligation to update such statements.

此外，任何前瞻性陳述僅代表我們截至本次錄音之日的觀點，不應被視為代表我們對任何後續日期的觀點。我們特此聲明，沒有義務更新此類聲明。

With that, I'll turn the call over to Yvonne. Yvonne?

這樣，我就把電話交給伊馮娜了。伊馮？

Thanks, Christine, and thank you, everyone, for joining the call today. Alnylam's Q3 results announced this morning demonstrate the exceptional progress we are making across all aspects of the business. As we continue to evolve into a top-tier bisect company, our focus remains on these three core pillars that we believe will drive sustainable growth and value creation for years to come.

謝謝克里斯汀，也謝謝大家今天參加電話會議。Alnylam今天早上公佈的第三季業績表明，我們在業務的各個方面都取得了卓越的進展。隨著我們不斷發展成為一流的二分之一公司，我們將繼續專注於這三大核心支柱，我們相信它們將在未來幾年推動永續成長和價值創造。

The first is TTR leadership. The AMVUTTRA launch delivered another strong quarter. It's still early, but we're very encouraged by the progress and dedicated to establishing long-term leadership in TTR.

首先是TTR的領導階層。AMVUTTRA的推出又帶來了一個強勁的季度業績。雖然現在還處於早期階段，但我們對取得的進展感到非常鼓舞，並致力於在 TTR 領域建立長期領導地位。

Next is growth to innovation, focused on the potential multibillion-dollar opportunities within our pipeline, and an R&D engine positioned to deliver sustainable innovation and value creation for many years to come.

接下來是向創新發展，重點關注我們產品線中潛在的數十億美元機遇，以及一個研發引擎，旨在為未來多年提供可持續的創新和價值創造。

The third element is strong financial performance, with robust top line growth and disciplined capital allocation, providing us with the opportunity to sustain profitability going forward. And of course, all of this is underpinned by a best-in-class team and our award-winning culture.

第三個要素是強勁的財務業績，包括穩健的營收成長和嚴謹的資本配置，這為我們提供了在未來保持獲利能力的機會。當然，這一切都離不開我們一流的團隊和屢獲殊榮的企業文化。

The quarterly results announced this morning represent strong execution on each of these fronts. Our commercial performance was driven by TTR franchise revenues of $724 million or 135% year-over-year growth, with growth largely attributable to the AMVUTTRA CM launch in the US, where we achieved total TTR revenues of $543 million, representing 194% year-over-year growth.

今天早上公佈的季度業績表明，公司在這些方面都取得了強勁的成效。我們的商業業績主要得益於 TTR 特許經營收入達到 7.24 億美元，年增 135%。這一成長主要歸功於 AMVUTTRA CM 在美國的推出，我們在美國實現了 TTR 總收入 5.43 億美元，年增 194%。

As Tolga will describe, the broad and balanced uptake in the second full quarter of launch drive an approximate doubling of TTR cardiomyopathy revenue compared to the prior quarter.

正如托爾加所描述的那樣，上市第二個完整季度的廣泛均衡的市場接受度，使得 TTR 心肌病變收入比上一季翻了一番。

In addition to these commercial results, we continue to advance our leading pipeline of RNAi therapeutics. Two new Phase 3 trials are getting underway. The ZENITH Phase 3 cardiovascular outcomes trial of zilebesiran in hypertension has initiated and the TRITON PN study of icrisiran in hATTR-PN will be initiating shortly to complement the TRITON CM study that was initiated last quarter.

除了這些商業成果之外，我們還在繼續推進我們領先的 RNAi 療法產品線。兩項新的三期臨床試驗即將啟動。針對高血壓患者的齊來貝西蘭 (zilebesiran) 的 ZENITH 3 期心血管結局試驗已經啟動，針對 hATTR-PN 患者的伊克西蘭 (icrisiran) 的 TRITON PN 研究也將很快啟動，以補充上個季度啟動的 TRITON CM 研究。

We're also excited by earlier-stage pipeline advancements in bleeding and neurologic disorders. And with regard to financial performance, our third quarter results show continued growth with $851 million in total net product revenues, up 13% year over year.

我們也對出血和神經系統疾病早期研發管線的進展感到興奮。在財務表現方面，我們第三季的業績顯示持續成長，總淨產品收入為 8.51 億美元，較去年同期成長 13%。

As a result, we've again increased our total net product revenue guidance for 2025 and from the range of $2.65 billion to $2.8 billion, to a revised range of $2.95 billion to $3.05 billion representing an increase of $275 million or 10% at the midpoint, underscoring our confidence in the AMVUTTRA TTR CM launch and our other commercial products for the remainder of the year. Now with our Alnylam piece of is by '25 era concluding soon.

因此，我們再次提高了 2025 年的總淨產品收入預期，從 26.5 億美元至 28 億美元的範圍修訂為 29.5 億美元至 30.5 億美元，其中點值增加了 2.75 億美元或 10%，這凸顯了我們對 AMVUTTRA TTR CM 的其他商業產品以及今年剩餘時間裡的其他商業產品的信心。現在，隨著我們 Alnylam 的作品在 '25 時代即將結束，

We're thrilled by this incredible execution over the past five years, reflecting tremendous progress on these ambitious goals. This is indeed a strong foundation on which to build our next phase of significant growth. and we look forward to harnessing this momentum.

在過去五年裡，我們取得了令人矚目的成就，這反映了我們在實現這些雄心勃勃的目標方面取得了巨大的進步，我們為此感到非常興奮。這的確為我們下一階段的顯著成長奠定了堅實的基礎，我們期待著充分利用這一勢頭。

With that, let me now turn the call over to Tolga for a review of our commercial performance. Tolga?

接下來，我將把電話交給托爾加，請他回顧我們的商業表現。托爾加？

Thanks, Yvonne, and good morning, everyone. It is a pleasure to show how we're continuing to bring Alnylam's transformative therapies to patients around the world.

謝謝伊馮，大家早安。很高興向大家展示我們如何繼續將 Alnylam 的變革性療法帶給世界各地的患者。

Following an exceptional Q2 continued on (inaudible) strong trajectory of growth and execution. We delivered $851 million in combined net product revenues representing 103% growth year over year and 27% growth versus the prior quarter. Our TTR franchise remains the primary growth engine. And we're also seeing continued momentum in our rare disease business.

繼第二季取得卓越成績後，公司繼續保持強勁的成長和執行勢頭。我們實現了 8.51 億美元的合併淨產品收入，年增 103%，季增 27%。我們的TTR特許經營權仍然是主要的成長引擎。同時，我們在罕見疾病業務方面也看到了持續的成長動能。

Let me start there. More than five years after launch, our rare disease portfolio continues to deliver meaningful impact for patients and steady performance for our business. In Q3, the rare portfolio achieved $127 million in sales, up 14% versus Q3 2024, driven largely by ongoing patient demand.

我就從這裡開始吧。推出五年多來，我們的罕見疾病產品組合持續為患者帶來有意義的影響，並為我們的業務帶來穩定的績效。第三季度，罕見疾病產品組合的銷售額達到 1.27 億美元，比 2024 年第三季成長 14%，主要得益於持續的病患需求。

While the timing of orders in our partner markets created some short-term shifts, the overall trajectory remains strong. I'm proud of the focus and dedication of our rare disease and partner teams who continue to reach patients with these two transformative medicines globally, even as much of the organization focuses on the TTR growth opportunity.

雖然合作夥伴市場的訂單時間安排造成了一些短期波動，但整體趨勢依然強勁。我為我們罕見疾病團隊和合作夥伴團隊的專注和奉獻精神感到自豪，他們繼續在全球範圍內為患者提供這兩種變革性藥物，即使公司的大部分精力都集中在 TTR 的成長機會上。

With that, let's review the TTR highlights. Q3 was another exceptional quarter for our TTR franchise, continuing the strong launch trajectory we saw in Q2.

接下來，讓我們回顧一下TTR的亮點。第三季對於我們的 TTR 系列產品來說又是一個卓越的季度，延續了我們在第二季度看到的強勁上市勢頭。

Global TTR net revenues reached [$72 million], up 33% versus the prior quarter and representing 135% growth year over year. This performance was primarily driven by an increase in US patient demand with an increase in US channel inventory more than offset by an increase in US gross to net deductions.

全球 TTR 淨收入達到 7,200 萬美元，較上一季成長 33%，較去年同期成長 135%。這一業績主要得益於美國患者需求的增加，但美國通路庫存的增加被美國毛利潤與淨利潤之比的增加所抵銷。

It is worth noting that the increase in gross to net deductions primarily impacted ONPATTRO, reducing US reported Q-over-Q growth in our hATTR-PN business relative to our recent quarterly run rate. In the US, net sales for our TTR franchise grew 42% quarter over quarter and 194% versus Q3 2024, reflecting continued robust adoption following the AMVUTTRA-ATTRCM label expansion.

值得注意的是，毛利扣除額與淨扣除額的增加主要影響了 ONPATTRO，導致我們 hATTR-PN 業務在美國報告的季度環比增長相對於我們最近的季度運行率有所下降。在美國，我們的 TTR 特許經營權的淨銷售額環比增長 42%，與 2024 年第三季度相比增長 194%，反映出在 AMVUTTRA-ATTRCM 標籤擴展之後，市場持續強勁增長。

Before we provide further color on the US launch, let me quickly share the ex US dynamics. Outside the US revenues grew 13% versus the prior quarter and 46% year over year, underscoring continued global momentum. Further, international AMVUTTRA ATTR-CM launches are anticipated across 2026, following the completion of local pricing and reimbursement reviews.

在詳細介紹美國市場的發布情況之前，讓我先快速分享一下美國以外地區的市場動態。美國以外地區的營收比上一季成長了 13%，年增了 46%，凸顯了全球業務的持續成長動能。此外，在完成當地定價和報銷審查後，預計 AMVUTTRA ATTR-CM 將於 2026 年在國際上推出。

Having said that, we're particularly pleased with the early progress in Japan where the CM launch is advancing well and tracking in line with leading launch analogs, a strong validation of AMVUTTRA's profile and first-line potential. In Germany, launch activities remain in the early stages as final reimbursement decisions continue, and we're encouraged by how the product differentiated profile is resonating at key treatment centers.

話雖如此，我們對日本的早期進展尤其感到滿意，CM發射進展順利，與領先的發射同類產品保持一致，這有力地驗證了AMVUTTRA的概況和一線潛力。在德國，由於最終的報銷決定仍在進行中，上市活動仍處於早期階段，但我們對該產品差異化的特點在主要治療中心引起的反響感到鼓舞。

More broadly, our international performance reflects the continued strength of our hATTR pull neuropathy legacy business, which remains robust despite new competition. Broader engagement in the category is expanding awareness and diagnosis, ultimately, benefiting patients and reinforcing Alnylam's leadership role in shaping the field. Building on our global presence, we're positioned to extend our momentum as AMVUTTRA ATTRCM launches expand worldwide.

更廣泛地說，我們的國際業績反映了我們 hATTR 拉動神經病變傳統業務的持續強勁，儘管面臨新的競爭，該業務依然保持穩健。更廣泛的參與正在擴大人們對該領域的認識和診斷，最終使患者受益，並鞏固 Alnylam 在塑造該領域的領導地位。憑藉我們的全球影響力，隨著 AMVUTTRA ATTRCM 在全球範圍內的推出，我們已做好準備，並繼續保持成長勢頭。

Now let's turn to the US on AMVUTTRA ATTRCM launch which recently completed its second full quarter and continues to build momentum.

現在讓我們來看看美國 AMVUTTRA ATTRCM 的推出情況，該專案最近完成了第二個完整季度，並繼續保持成長勢頭。

In Q3, our US TTR franchise across both PN and CM indications, delivered $543 million in net product revenues representing an increase of approximately $160 million versus the prior quarter. If we assume steady and consistent growth of $50 million quarter over quarter in the pulmonaropathy-based business, then we estimate the CM indication represents approximately $300 million of net product revenues this quarter or doubled from Q2. This reflects sustained launch momentum in AMVUTTRA ATTRCM with patient demand roughly doubling compared to Q2 and as awareness and physician adoption continue to grow.

第三季度，我們在美國 TTR 產品線（涵蓋 PN 和 CM 適應症）的淨產品收入為 5.43 億美元，比上一季增加了約 1.6 億美元。如果我們假設肺病業務每季穩定成長 5,000 萬美元，那麼我們估計 CM 適應症在本季將帶來約 3 億美元的淨產品收入，比第二季翻了一番。這反映了 AMVUTTRA ATTRCM 持續的上市勢頭，患者需求與第二季度相比大約翻了一番，而且認知度和醫生採納率也在不斷提高。

Our strength is built on three key pillars as part of our launch strategy. First, health system setup. It is not complete. Nearly all of our 170 priority health systems are now using AMVUTTRA, driving broad utilization, combined with our extensive treatment site network, roughly 90% of the US patients can receive their AMVUTTRA treatment within 10 miles of (inaudible) anywhere in the US and meaningful milestone and accessibility.

這是我們產品上市策略的三大支柱。首先，建立醫療衛生系統。尚未完成。我們 170 個重點醫療系統中的幾乎所有現在都在使用 AMVUTTRA，推動了廣泛應用，再加上我們廣泛的治療點網絡，大約 90% 的美國患者可以在美國任何地方 10 英里範圍內接受 AMVUTTRA 治療，這是一個重要的里程碑和可及性。

So again, the health system setup is effectively complete. As such, we plan to no longer report on this launch enabler on future calls. Second, access remains strong. Payer coverage is broad and nearly all patients have access to AMVUTTRA as a first-line treatment option, meaning these patients have no step edits. Of similar importance most patients pay zero out of pocket.

所以，醫療衛生系統建設其實已經完成。因此，我們計劃在以後的電話會議上不再報告這項啟動推動因素。其次，准入條件依然良好。支付者涵蓋範圍廣泛，幾乎所有患者都可以將 AMVUTTRA 作為第一線治療方案，這意味著這些患者無需接受階梯式治療。同樣重要的是，大多數患者無需自付任何費用。

Finally, with health system setup and access and affordability in place, we are focused on treatment choice and the profile of our AMVUTTRA continues to resonate. We're seeing broad and balanced adoption across new diagnosed patients and those progressing on stabilizers in both academic and community settings.

最後，隨著醫療體系的建立、可近性和可負擔性到位，我們專注於治療選擇，而我們的 AMVUTTRA 的形像也繼續引起共鳴。我們看到，無論是在學術機構還是社區環境中，新確診的患者和正在接受穩定劑治療的患者都得到了廣泛而均衡的採用。

Subscriber growth also remains robust. Having reviewed the three strategic pillars, we're executing and delivering on them. Patient demand roughly doubled quarter over quarter, reflecting strong, sustained momentum for the AMVUTTRA-ATTRCM and US launch.

用戶成長依然強勁。在審視了三大策略支柱之後，我們正在執行並落實這些支柱。患者需求季增約一倍，反映出 AMVUTTRA-ATTRCM 在美國上市的強勁、持續動能。

In summary, it is still early in the journey, but the results to date highlight the substantial long-term opportunity ahead and underscore our strong positioning for leadership in this expanding underserved TTR category.

總而言之，雖然目前仍處於起步階段，但迄今為止的成果凸顯了未來巨大的長期機遇，並強調了我們在這一不斷擴大的、服務不足的 TTR 類別中的強大領導地位。

Looking ahead, the majority of ex US launches are expected to begin in 2016 as pricing and reimbursement processes wrap up, extending our global reach and providing a measured contribution to launch momentum. We continue to invest in the TTR category, advancing science, enhancing patient experience, and building a durable foundation. Pushkal and the R&D organization are leading that chapter.

展望未來，隨著定價和報銷流程的完成，預計大部分美國以外的產品將於 2016 年開始上市，這將擴大我們的全球影響力，並為上市勢頭做出實際貢獻。我們持續投資於 TTR 類別，推動科學發展，提升病患體驗，並建立穩固的基礎。Pushkal 和研發機構正在引領這項進程。

With that, I'll hand it over to you. Pushkal?

這樣，我就把它交給你了。普什卡爾？

Thank you, Tolga, and good morning, everyone. In support of AMVUTTRA's strong launch in ATTR-CM, we continue to share new data from the HELIOS-B study that further underscore the unique and compelling profile of this medicine with the aim of cementing AMVUTTRA as the treatment of choice for patients with ATTR cardiomyopathy.

謝謝你，托爾加，大家早安。為了支持 AMVUTTRA 在 ATTR-CM 中的強勁上市，我們繼續分享 HELIOS-B 研究的新數據，進一步強調了該藥物獨特而引人注目的特性，旨在鞏固 AMVUTTRA 作為 ATTR 心肌病變患者首選治療方案的地位。

To that end, as shown on the left, at ESC, we presented new data from HELIOS PE that demonstrates the sustained benefits of vutrisiran through up to 48 months, which includes 12 months from the open-label extension. Specifically, as compared to placebo, which substantially reduced the risk of the composite of all-cause mortality or first cardiovascular event by 37% in the overall population and 42% in the monotherapy group.

為此，如左圖所示，在 ESC 上，我們展示了來自 HELIOS PE 的新數據，該數據表明 vutrisiran 的持續益處可長達 48 個月，其中包括開放標籤擴展的 12 個月。具體而言，與安慰劑相比，該藥物使整體人口全因死亡率或首次心血管事件的複合風險降低了 37%，單藥治療組降低了 42%。

More recently, at HFSA, as shown on the right, we shared important new data from the double-blind period demonstrating that vutrisiran treatment was associated with a lower rate of gastrointestinal adverse events versus placebo across the overall vutrisiran monotherapy and baseline tafamidis treatment groups with reductions of 37% to 49%.

最近，在 HFSA 上（如右圖所示），我們分享了雙盲期的重要新數據，顯示與安慰劑相比，vutrisiran 治療與胃腸道不良事件發生率降低相關，在整個 vutrisiran 單藥治療組和基線 tafamidis 治療組中，胃腸道不良事件發生率降低了 37% 至 49%。

This observation is quite important, so that suggests vutrisiran may reduce GI symptoms, which as you can see from the placebo data, we're seen in approximately 40% of patients. These symptoms arise from the multisystemic nature of ATTR cardiomyopathy and are a major source of concern for patients with this disease.

這項觀察結果非常重要，這表明 vutrisiran 可能減輕胃腸道症狀，正如您從安慰劑數據中看到的那樣，我們在大約 40% 的患者中觀察到了這些症狀。這些症狀是由 ATTR 心肌病變的多系統性引起的，是該疾病患者的主要擔憂來源。

With these continued insights from HELIOS B, we're excited about the prospects for RNAi therapeutics to become the standard of care in TTR amyloidosis. Nucresiran, our next-generation silencer may offer even greater TTR knockdown with subcutaneous biannual dosing is now being evaluated in the TRITON Phase 3 program.

憑藉 HELIOS B 的持續研究成果，我們對 RNAi 療法有望成為 TTR 澱粉樣變性的標準療法感到興奮。Nucresiran 是我們的下一代抑制劑，透過皮下注射每半年一次，可以更有效地抑制 TTR，目前正在 TRITON 3 期專案中進行評估。

We announced last quarter the initiation of the TRITON CM trial in cardiomyopathy patients. Today, I'm happy to share additional details about the TRITON PN trial in hereditary TTR polyneuropathy patients, which we'll be initiating shortly. This will be an open-label trial of Nucresiran in approximately 125 patients with hATTR-PN.

我們上個季度宣布啟動針對心肌病變患者的 TRITON CM 試驗。今天，我很高興與大家分享有關 TRITON PN 治療遺傳性 TTR 多發性神經病變患者的試驗的更多細節，我們將很快啟動這項試驗。這將是一項針對約 125 名 hATTR-PN 患者的 Nucresiran 開放標籤試驗。

Patients will be randomized four to one to receive either nucresiran dosed every six months, or to a reference arm of vutrisiran, dosed every three months. The primary endpoint is the change from baseline in the modified neuropathy impairment score or mNIS+7 at month nine in the nucresirian par as compared to the placebo arm from the APOLLO Phase 3 trial of patisiran.

患者將以 4:1 的比例隨機分組，分別接受每六個月一次的 nucresiran 治療，或每三個月一次的 vutrisiran 治療（作為參考組）。主要終點是與安慰劑組相比，接受核仁治療的患者在接受帕替西蘭治療的 APOLLO 3 期試驗中，第 9 個月時改良神經病變損傷評分 (mNIS+7) 較基線的變化。

You might recall that this is essentially the same study design we utilized in our HELIOS-A pivotal study of vutrisiran in hATTR-PN, which led to its initial approval in that disease setting. We expect top line results from TRITON PN in 2028 look forward to sharing additional details as the trial gets underway. Now moving on to another exciting program.

您可能還記得，這與我們先前在 hATTR-PN 中 vutrisiran 的 HELIOS-A 關鍵性研究中採用的研究設計基本相同，該研究促成了 vutrisiran 在該疾病領域的首次獲批。我們預計 TRITON PN 將於 2028 年公佈主要結果，並期待在試驗開始後分享更多細節。接下來我們將介紹另一個精彩的節目。

We made great progress this quarter with our zilebesiran program in hypertension. This program represents an amazing opportunity to address some of the major shortcomings of existing antihypertensive therapies.

本季度，我們在高血壓治療方面，齊來貝西蘭計畫取得了巨大進展。該計畫為解決現有降血壓療法的一些主要缺陷提供了一個絕佳的機會。

By targeting angiotensinogen upstream of the RAS cascade we believe we can help more patients get to goal, not only in terms of the quantity of blood pressure lowering but also the quality of blood pressure control, reducing blood pressure variability, improving adherence, and restoring nocturnal dipping.

我們相信，透過靶向 RAS 級聯上游的血管緊張素原，可以幫助更多患者達到目標，不僅在降低血壓的量上，而且在血壓控制的品質上，減少血壓變異性，提高依從性，並恢復夜間血壓下降。

Ultimately, we believe continuous control of blood pressure will drive long-term improvements in cardiovascular outcomes. At ESC in August and shown on the right, we shared results from the CARDIO II Phase 2 study.

我們最終相信，持續控制血壓將推動心血管疾病預後的長期改善。在 8 月的 ESC 會議上（如圖），我們分享了 CARDIO II 2 期研究的結果。

As you can see, treatment with zilebesiran resulted in clinically meaningful reductions in (inaudible) is tolled blood pressure in patients with uncontrolled hypertension and high cardiovascular risk at the month three primary endpoint with continuous control sustained through month six. Moreover, the treatment effect was further enhanced in a biologically based enriched subgroup of patients.

如您所見，使用齊來貝西蘭治療在第三個月的主要終點時，未控制的高血壓和高心血管風險患者的血壓（聽不清楚）得到了具有臨床意義的降低，並且持續控製至第六個月。此外，在生物學特徵顯著增強的患者亞群中，治療效果進一步提高。

With these results, Cardia I met the objective of informing the design, patient population and dose for the global Phase 3 cardiovascular outcomes trial, Zenith. Zenith is a cardiovascular outcomes trial that will enroll approximately 11,000 patients to evaluate zilebesiran at a dose of 300 milligrams given every six months compared to placebo in patients with uncontrolled hypertension with either established or at high risk for cardiovascular disease on two or more antihypertensives.

憑藉這些結果，Cardia I 達到了為全球 3 期心血管結果試驗 Zenith 提供設計、患者族群和劑量資訊的目標。Zenith 是一項心血管結局試驗，將招募約 11,000 名患者，評估每六個月服用 300 毫克齊來貝西蘭與安慰劑相比，對服用兩種或兩種以上降血壓藥且患有未控制高血壓、確診或有較高心血管疾病風險的患者的療效。

The endpoint is a vent trip with a minimum follow-up of two years, and we expect to launch, assuming a successful study and regulatory approval around 2030.

終點是進行呼吸器植入，至少追蹤兩年。我們預計，如果研究成功並獲得監管部門批准，將在 2030 年左右推出該產品。

I'm also excited to share an update today on our ALN 6400 development program. ALN-6400 targets plasminogen, and we believe it has the potential to be a universal hemostatic agent that can address significant unmet needs across a range of bleeding disorders effectively becoming a pipeline and a product.

今天我也很高興與大家分享我們ALN 6400開發專案的最新進展。ALN-6400 針對纖溶酶原，我們相信它有潛力成為一種通用止血劑，能夠有效解決一系列出血性疾病中尚未滿足的重大需求，並最終成為研發管線和產品。

Plasminogen is a genetically validated target, high circulating levels are associated with increased bleeding. And conversely, individuals with loss of function variants have reduced rates of bleeding. Importantly, loss of function is not associated with the increased risk of thrombosis.

纖溶酶原是一個經過基因驗證的靶點，其高循環水平與出血增加有關。反之，功能缺失變異的個體出血率降低。重要的是，功能喪失與血栓形成風險增加無關。

As we believe that by lowering plasminogen with ALN-6400, we potentially can slow down the process of fibrinolysis thereby stabilizing clots and preventing bleeding without increasing the risk of thrombosis. Today, we're announcing the first indication we'll focus on with ALN-6400, hereditary hemorrhagic tolangictasia, HHT.

我們相信，透過 ALN-6400 降低纖溶酶原，我們有可能減緩纖維蛋白溶解過程，從而穩定血栓並防止出血，而不會增加血栓形成的風險。今天，我們宣布 ALN-6400 的第一個適應症，即遺傳性出血性毛細血管擴張症 (HHT)。

HHT is the second most common inherited bleeding disorder, affecting individuals of all ages. 90% of HHT patients live with recurrent nose bleeds which can be severe and life-threatening and many experienced gastrointestinal and heavy menstrual bleeding as well.

遺傳性出血性毛細血管擴張症（HHT）是第二常見的遺傳性出血性疾病，可影響所有年齡層的人。 90%的HHT患者會反覆出現鼻出血，有時出血量大甚至危及生命，許多患者還會出現胃腸道出血和月經過多。

And importantly, more than half of patients face iron deficiency anemia. So this is a burdensome condition and from one for which there are very limited treatment options. Importantly, we've already demonstrated initial proof of mechanism for this program in healthy volunteers in Phase 1.

更重要的是，超過一半的患者患有缺鐵性貧血。所以這是一種很棘手的疾病，而且治療選擇非常有限。重要的是，我們已經在 1 期臨床試驗中對健康志願者進行了初步的機制驗證。

On the right are the results from an ex vivo assay of fibrinolysis from our Phase 1 study and shows in the top panel without ALN-6400, clot formation represented by the dark blue area quickly dissipates. Whereas with ALN-6400, there is an antifibrinolytic effect as represented by the dark blue area, which extends for a much longer time, and this effect is maintained after 43 days.

右側是我們 1 期研究中體外纖維蛋白溶解試驗的結果，頂部面板顯示，在沒有 ALN-6400 的情況下，深藍色區域代表的血栓形成迅速消散。而 ALN-6400 則具有抗纖溶作用，如深藍色區域所示，這種作用持續時間更長，並且在 43 天後仍能維持這種作用。

We've now moved ALN-6400 into a Phase 2 trial in HHT patients and look forward to providing updates as this program progresses. We also continue to advance new programs into clinical development building a pipeline that has the potential to drive sustainable growth and long-term value creation.

我們已將 ALN-6400 推進到 HHT 患者的 2 期試驗階段，並期待隨著該計畫的進展提供最新資訊。我們也不斷推進新項目進入臨床開發階段，建構能夠推動永續成長和長期價值創造的產品線。

Today, for example, we announced the initiation of a Phase 1 trial of ALN-5288, which targets MAPT or TAO for Alzheimer's disease and potentially other rare (inaudible) . The trial will evaluate the drug safety, tolerability, pharmacokinetics and pharmacodynamics in adult patients with Alzheimer's disease.

例如，今天我們宣布啟動ALN-5288的I期臨床試驗，該藥物靶向MAPT或TAO，用於治療阿茲海默症以及其他潛在的罕見疾病。（聽不清楚）該試驗將評估該藥物在患有阿茲海默症的成年患者中的安全性、耐受性、藥物動力學和藥效學。

With that, let me now turn it over to Jeff to review our financial results and upcoming milestones. Jeff?

接下來，我將把發言權交給傑夫，讓他來回顧我們的財務表現和即將到來的里程碑。傑夫？

Thanks, Pushkal, and good morning, everyone. I'm pleased to be presenting a summary of Alnylam's Q3 2025 financial results and discussing our full year upgraded guidance.

謝謝普什卡爾，大家早安。我很高興向大家介紹 Alnylam 2025 年第三季的財務業績概要，並討論我們全年業績的上調預期。

Let's begin with a summary of our P&L results for Q3 2025 compared with the same period in 2024. Total product revenues for the quarter were $851 million or 103% growth versus 2024, driven by 135% growth in our TTR franchise, primarily from the continued strong performance of the US launch of AMVUTTRA and ATTR cardiomyopathy.

讓我們先來總結一下 2025 年第三季與 2024 年同期相比的損益結果。本季產品總營收為 8.51 億美元，比 2024 年成長 103%，主要得益於 TTR 產品線 135% 的成長，而這又主要歸功於 AMVUTTRA 和 ATTR 心肌病變在美國市場的持續強勁表現。

Collaboration revenue for the quarter was $352 million, representing a $294 million increase when compared with last year. The increase was primarily due to revenue recognized under our collaboration and license agreement with Roche, including $300 million of milestone revenue associated with the dosing of the first patient in our ZENITH Phase 3 cardiovascular outcomes trial with (inaudible) .

本季合作營收為 3.52 億美元，比去年同期成長 2.94 億美元。此次成長主要歸功於我們與羅氏的合作與授權協議下確認的收入，其中包括與我們ZENITH III期心血管結局試驗中首例患者給藥相關的3億美元里程碑收入。（聽不清楚）

Royalty revenue for the quarter was $46 million representing a doubling compared with last year, driven by higher (inaudible) sales as Novartis continues to successfully grow the product globally. Gross margin on product sales was 77% for the quarter, compared with 80% in the third quarter of 2024. The decrease in margin was primarily driven by increased royalties on AMVUTTRA as higher revenues in 2025 resulted in an increase in the royalty rate compared with last year.

本季特許權使用費收入為 4,600 萬美元，比去年翻了一番，這主要得益於諾華公司在全球範圍內持續成功拓展該產品，導致銷售額（聽不清楚）成長。本季產品銷售毛利率為 77%，而 2024 年第三季為 80%。利潤率下降的主要原因是 AMVUTTRA 的特許權使用費增加，因為 2025 年更高的收入導致特許權使用費率比去年有所提高。

For the fourth quarter, our gross margin on product sales is expected to decrease as the applicable AMVUTTRA royalty rates increased further, driven by higher expected sales of AMVUTTRA. Our non-GAAP R&D expenses of $310 million increased 23% compared to last year, primarily driven by costs associated with the initiation of multiple Phase 3 clinical studies including the Zenith Phase 3 cardiovascular outcomes trial for zilebesiran and the TRITON CM Phase 3 study for ducrisiran.

預計第四季度，由於 AMVUTTRA 的預期銷售額增加，適用的 AMVUTTRA 特許權使用費率進一步提高，我們的產品銷售毛利率將會下降。我們的非GAAP研發費用為3.1億美元，比去年增加了23%，主要原因是啟動了多項3期臨床研究的相關成本，包括zilebesiran的Zenith 3期心血管結果試驗和ducrisiran的TRITON CM 3期研究。

Our non-GAAP SG&A expenses of $263 million increased 35% compared to last year, primarily driven by increased headcount and other investments in support of the AMVUTTRA-ATTR cardiomyopathy launch in the US. Our non-GAAP operating income for the quarter was $476 million, representing a $507 million increase compared with last year, driven primarily by strong top line results both in product sales, a well's revenue from collaborations as previously highlighted.

我們的非GAAP SG&A費用為2.63億美元，比去年增加了35%，主要原因是員工人數增加以及為支持AMVUTTRA-ATTR心肌病變在美國上市而進行的其他投資。本季非GAAP營業收入為4.76億美元，比去年同期增長5.07億美元，主要得益於產品銷售和合作項目收入的強勁增長，正如之前所強調的那樣。

We continue to be pleased with the progress we are making towards achieving our non-GAAP operating profitability guidance in 2025. We ended the quarter with cash, cash equivalents and marketable securities of $2.7 billion compared with a similar amount at the end of 2024. Cash for the quarter was impacted by our refinancing in September.

我們對在實現 2025 年非 GAAP 營運獲利目標方面取得的進展感到滿意。本季末，我們持有的現金、現金等價物和有價證券為 27 億美元，而 2024 年底的金額與之相近。受9月再融資的影響，本季現金流受到影響。

We raised more than $600 million via the issuance of new convertible notes, which was more than offset by the use of $1.1 billion of cash to repurchase a large portion of our convertible senior notes due in 2027.

我們透過發行新的可轉換票據籌集了超過 6 億美元，但這筆資金被 11 億美元的現金用於回購 2027 年到期的大部分可轉換優先票據所抵消。

Additionally, we also entered into a $500 million revolving credit facility, providing a new source of flexible liquidity if necessary. Now I'd like to turn to our financial guidance for 2025 and where we are increasing our net product revenue guidance driven by the strong US launch performance of AMVUTTRA and ATTR cardiomyopathy with specific details as follows.

此外，我們還簽訂了 5 億美元的循環信貸協議，以便在必要時提供新的靈活流動性來源。現在我想談談我們對 2025 年的財務預期，以及在 AMVUTTRA 和 ATTR 心肌病變在美國強勁的上市表現推動下，我們提高了淨產品收入預期，具體細節如下。

We are increasing our net product revenue guidance from a range of $2.65 billion to $2.8 billion to a revised range of $2.95 billion to $3.05 billion representing a $275 million or 10% increase from the midpoint of the prior guidance to the midpoint of the updated guidance. The combined full year growth compared to 2024 is an 82% increase at the midpoint of the guidance range.

我們將淨產品收入預期從 26.5 億美元至 28 億美元上調至 29.5 億美元至 30.5 億美元，較先前預期的中點增加了 2.75 億美元，增幅達 10%。與 2024 年相比，全年綜合成長率為 82%（以指導範圍的中點計算）。

On a franchise level, the guidance is broken down as follows: we are increasing our total TTR guidance range from $2.17 billion to $2.275 billion to a revised range of $2.475 billion to $2.525 billion, representing a 12% increase at the midpoint.

從特許經營層面來看，指導意見細分如下：我們將總 TTR 指引範圍從 21.7 億美元至 22.75 億美元上調至修訂後的 24.75 億美元至 25.25 億美元，其中點增長了 12%。

We are reiterating our guidance range for our total rare franchise of $475 million to $525 million. We are also narrowing the range of our non-GAAP operating expense guidance to $2.15 billion to $2.2 billion as we expect to end the year at the upper end of our original 2025 operating expense guidance.

我們重申我們對稀有特許經營權總收入的預期範圍為 4.75 億美元至 5.25 億美元。同時，我們將非GAAP營運費用預期範圍縮小至21.5億美元至22億美元，因為我們預計今年的營運費用將達到我們最初2025年營運費用預期的上限。

The remainder of our financial guidance, including collaboration and royalty revenue and non-GAAP operating income remains unchanged. Turning now from financials to our key remaining goals for 2025. As Pushkal mentioned earlier, the TRITON TN trial of nucresiran and hATTR-PN will initiate shortly.

其餘財務預期，包括合作和特許權使用費收入以及非GAAP營業收入，維持不變。現在我們從財務狀況轉向2025年剩餘的關鍵目標。正如 Pushkal 之前提到的，NUCRESIRA 和 HATTR-PN 的 TRITON TN 試驗即將開始。

We also expect to initiate a Phase 2 trial of (inaudible) in Alzheimer's disease. Let me now turn it back to Christine to coordinate our Q&A session. Christine?

我們也計劃啟動一項針對阿茲海默症（聽不清楚）的第二期臨床試驗。現在我把時間交還給克莉絲汀，讓她來協調我們的問答環節。克里斯汀？

Thank you, Jeff. Operator, we will now open the call for questions. To those dialed in, we would like to ask you to limit yourself to one question each and then get back in the queue if you have additional questions.

謝謝你，傑夫。接線員，現在開始接受提問。已撥入電話的各位，請每人限提一個問題，如有其他問題，請重新排隊。

(Operator Instructions) Salveen Richter, Goldman Sachs.

（操作說明）薩爾文·里希特，高盛。

Could you just speak with regard to AMVUTTRA how the momentum is going in the first line versus switches population and maybe talk about any combo use? And any clarity here on ex US pricing would be helpful as well.

您能否談談 AMVUTTRA 中第一線對陣第二線的勢頭如何，以及是否有任何連招使用情況？此外，如果能提供美國以外地區的定價信息，也將不勝感激。

Yes. This is a great question. We're obviously really pleased with the continued momentum that we're seeing with respect to growth in our TTR business, particularly having doubled the patient demand volume for AMVUTTRA cardiomyopathy in the US. But Tolga, why don't you take the question around.

是的。這是一個很好的問題。顯然，我們對 TTR 業務持續成長的勢頭感到非常高興，尤其是美國 AMVUTTRA 心肌病變患者需求量翻了一番。但是托爾加，你為什麼不把這個問題帶出去問呢？

Absolutely. Look, we're really pleased with another strong quarter. As we indicated, demand doubled in cardiomyopathy and utilization remains very broad and balanced. So let me double-click on that. What we're really seeing is an adoption across both academic and community settings and also from a wide range of prescribers and patient types.

絕對地。你看，我們對又一個強勁的季度業績非常滿意。正如我們所指出的，心肌病變的需求翻了一番，而且利用率仍然非常廣泛和均衡。那我雙擊一下看看。我們看到的是，無論是在學術界還是社區，無論是在處方醫生還是患者群體中，這種做法都得到了廣泛應用。

And essentially, that really demonstrates a very healthy uptick. Within that, what we also like to see is what we're seeing is we're getting in a place of very competitive setting in terms of first line. And our first-line share continues to grow quarter over quarter. And we're obviously maintaining a clear leadership in second line among those patients that are progressing or not responding to a stabilizer. So that breadth and balance gives us real confidence in the durability of (inaudible) momentum.

從本質上講，這確實表明出現了非常健康的成長。其中，我們也樂於看到的是，我們在一線隊方面正處於一個競爭非常激烈的環境中。我們的一線市佔率持續環比成長。顯然，對於病情進展或對穩定劑無反應的患者，我們在二線治療領域中保持著明顯的領先地位。因此，這種廣度和平衡讓我們對（聽不清楚）勢頭的持久性充滿信心。

And in terms of our ex US pricing, we're still continuing to engage with a broad range of countries in terms of pricing and reimbursement. What we've so far seen is a really compelling pricing profile for in Japan.

至於美國以外的定價，我們仍在繼續與許多國家就定價和報銷事宜進行磋商。目前我們看到的是日本市場極具吸引力的定價策略。

We're also launched in Germany, but we're actually in the early stages of pricing and reimbursement negotiations. And obviously, what we're really trying to make sure is the right value for our innovation is being recognized in Europe as well as we have in the US. And that remains to be seen throughout '26.

我們也在德國推出了服務，但目前仍處於定價和報銷談判的早期階段。顯然，我們真正想要確保的是，我們的創新在歐洲也能像在美國一樣獲得應有的認可。而這一切還有待2026年全年觀察。

Yes. And there's a question on combination use. And I think, look, we're seeing some use in combination. But overall, the majority of the use is as a monotherapy. And as we've always said, the (inaudible) goes generic, we anticipate that we'll see increasing combination use.

是的。還有一個關於組合使用的問題。而且我認為，你看，我們看到了一些組合使用的現象。但總體而言，大多數情況下都是作為單一療法。正如我們一直所說，隨著（聽不清楚）通用化，我們預計我們將看到組合使用的情況越來越多。

Thanks for your question. Next question.

謝謝你的提問。下一個問題。

Paul Matas, Stifel.

Paul Matas，Stifel。

This is Julian on for Paul. Just a quick question again on AMVUTTRA. I guess like what gives you confidence that you're going to continue to see an acceleration in patient adds next year and going into the end of this year? And also, it seems like there was somewhat of a contribution from switches from ONPATTRO in the US this quarter versus last quarter.

這裡是朱利安替保羅發言。關於AMVUTTRA，我還有一個小問題。我想問的是，是什麼讓您有信心在明年以及今年年底之前繼續看到患者數量加速增長？此外，與上季相比，本季來自美國 ONPATTRO 的轉換似乎也扮演了一定的角色。

Again, any color on patient switches from stabilizers would really be helpful. And then just really quick on (inaudible) , can you just talk about what led to the decision to pursue that program and your confidence in the target. Does this say anything about your ALN-APP program in all sites as well?

再次強調，如果能給病人從穩定器切換到其他設備時使用某種顏色的指示燈，那就太好了。然後，關於（聽不清楚），您能簡單談談是什麼促使您決定參加這個項目，以及您對目標的信心嗎？這是否也說明了你們在所有站點的ALN-APP專案的情況？

Okay. So a couple of questions here, and we'll try and unpack them Look, I think what Tolga shared in the prepared remarks were really the features of a very strong launch, as obviously, we're delighted by them. We do see a lot more potential ahead of us. Tolga, do you want to --

好的。這裡有幾個問題，我們會嘗試解答。你看，我認為托爾加在準備好的發言稿中分享的內容，確實展現了一次非常成功的發布會的特點，顯然，我們對此感到非常高興。我們看到未來還有很大的發展潛力。托爾加，你想…--

Yes. Maybe I can take that on ONPATTRO contribution question right off the bat. Look, I think actually, you're probably misinterpreting that ONPATTRO declined from the prior quarter, and that really was driven by the ONPATTRO's favorability from last quarter's onetime Medicaid adjustment, which didn't repeat. So that really is the dynamic.

是的。或許我可以直接回答 ONPATTRO 貢獻的問題。你看，我認為你實際上可能誤解了 ONPATTRO 較上一季度下降的情況，而這實際上是由於 ONPATTRO 受到上一季度一次性 Medicaid 調整的影響，而這種調整並沒有再次發生。這就是問題的本質。

We're actually seeing a pretty steady quarter-over-quarter maintenance of our ONPATTRO business, albeit very minimal. And also, our PM business remains very, very stable. So in terms of our ability to actually continue to robustly continue this momentum. Look, we're only two quarters into this launch. And we've already raised guidance twice.

實際上，我們看到 ONPATTRO 業務每季都保持著相當穩定的水平，儘管增幅非常小。而且，我們的產品管理業務依然非常非常穩定。所以，就我們能否繼續保持這種強勁勢頭而言。你看，我們才剛啟動了兩個季度。我們已經兩次上調了指導意見。

I think that really speaks volume about the depth and the durability and our confidence in how we see these categories continue to grow. And as I mentioned, I think we do have a very balanced and broad uptick. And we certainly look forward to increasing our presence in first line, which is highly competitive as it is and maintain our leadership in those patients that are progressing on a stabilizer.

我認為這充分體現了我們對這些類別持續成長的信心、信心和持久性。正如我之前提到的，我認為我們確實看到了一個非常均衡且廣泛的成長。我們當然期待在競爭非常激烈的首選治療領域擴大市場份額，並保持我們在病情穩定的患者群體中的領先地位。

Thanks, Tolga. And I think the question with respect to (inaudible) implications for APP. Pushkal, would you take that one?

謝謝你，托爾加。我認為這個問題與 APP 的（聽不清楚）影響有關。普什卡爾，你願意接受那個嗎？

Yes, absolutely. Look, we're very excited about bringing Matto the clinic. I think as a starting point, this just highlights what we think is the potential of RNA interference therapeutics to have really substantial effect in neurodegenerative diseases.

是的，絕對的。瞧，我們很高興能把馬托診所帶到這裡。我認為，這首先突顯了我們認為 RNA 幹擾療法在治療神經退化性疾病方面具有的真正實質作用。

So along with APP, we have Huntington's program, APT, our colleagues at Regeneron are advancing SOG. We've just been very excited about the -- our delivery -- our ability to deliver safely and with infrequent dosing.

所以除了 APP 之外，我們還有亨廷頓氏症計畫 APT，我們在 Regeneron 的同事們正在推進 SOG 計畫。我們對——我們的交付——我們能夠安全、低頻次地交付藥物的能力感到非常興奮。

(inaudible) is a genetically validated target both in Alzheimer's disease and primary (inaudible) , which are all neurodegenerative diseases where we get these neurofibrillary tangles that cause neurodegeneration and cognitive decline in patients. So very excited.

（聽不清楚）是阿茲海默症和原發性（聽不清楚）中經過基因驗證的靶點，這些都是神經退化性疾病，在這些疾病中，我們獲得了神經纖維纏結，導致患者出現神經退化和認知能力下降。太激動了！

We're building really a portfolio of therapeutics that we think hopefully can address some of the most intractable diseases in mankind. And I think this just speaks to the strength of the platform and hopefully being able to deliver a second and additional pillars in 2030 and beyond.

我們正在建立一個治療藥物組合，希望能夠解決人類一些最棘手的疾病。我認為這正體現了該平台的實力，希望我們能夠在 2030 年及以後推出第二個及其他支柱。

I think that's great. Thank you for asking a pipeline question. We really do believe that not only who we bought a very well developing revenue trajectory with respect to our TTR franchise, but we really do have a clinical pipeline that has a number of multibillion opportunities that we're prosecuting in fiscals, organizations, expeditious as began, clearly being able to help patients with severe neurodegenerative diseases would be an incredible achievement. So thank you, Pushkal. Next question.

我覺得這很棒。感謝您提出有關管道的問題。我們真心相信，我們收購的不僅是 TTR 特許經營權方面發展良好的收入軌跡，而且我們還擁有一個臨床研發管線，其中包含許多數十億美元的機會，我們正在以最快的速度在各個財政年度和組織中推進這些機會，顯然，能夠幫助患有嚴重神經退行性疾​​病的患者將是一項了不起的成就。所以，謝謝你，普什卡爾。下一個問題。

Tazeen Ahmad, Bank of America.

塔津·艾哈邁德，美國銀行。

I wanted to get some color on payer dynamics as you get into the launch now Lari,like your third or fourth quarter in almost -- how are you getting feedback from payers or survey work seems to indicate that we're not seeing any pushback yet even as the drug has adopted to formulary.

Lari，現在差不多到了上市的第三或第四個季度了，我想了解一下支付方的動態——你是如何從支付方那裡獲得反饋的？或者調查工作似乎表明，即使該藥物已被納入處方集，我們還沒有看到任何阻力。

But as you're thinking about or currently negotiating 2026 status, can you share with us some of the feedback that you're getting from payers? Is there going to be any risk of payers preferring a stabilizer to a silencer or at least ordering which of the products that are currently available, they might prefer.

但是，當您考慮或目前正在協商 2026 年的狀況時，您能否與我們分享您從付款方那裡得到的一些回饋？付款方是否會更傾向於選擇穩定器而不是消音器，或者至少在訂購現有產品時，是否會更傾向於選擇他們喜歡的產品？

Yes. No, that's a great question. I mean, look, we're delighted that we really had no payer headwinds. And perhaps, Tolga, do you want to speak to the outlook as we see it as we go into 2020.

是的。不，這是一個很好的問題。我的意思是，你看，我們很高興真的沒有遇到任何付款方面的阻力。托爾加，或許你想談談我們對 2020 年的展望？

Hi Tazeen, I think it's really good to hear that you guys feel like it's already been a year almost. It's actually only two quarters that we've had the launch -- and as Ivan indicated, that what we're seeing is really headwinds in terms of every actually payer piece, whether it's fee-for-service, Medicare Advantage or even in the commercial setting. I know there has been a lot of debate around whether we would be step edited or whether the burden on the patients in terms of co-pay would be high.

嗨，Tazeen，聽到你們覺得好像已經快一年了，我覺得真的很好。實際上，我們的產品上市才兩個季度——正如伊万所指出的，我們看到的是，在每一個實際的支付方方面面都存在著真正的阻力，無論是按服務收費、Medicare Advantage，甚至是商業保險。我知道一直以來都有很多爭論，爭論的焦點在於我們是否會進行分階段編輯，以及患者在共同支付方面的負擔是否會很重。

And what we're really pleased to see, as anticipated based on our experience in the PN, payers actually understand and they appreciate the value that this product brings. Clearly highly differentiated in a disease that's actually fatal and highly progressing. And both payers and physicians really appreciate that this disease needs to be treated early and effectively.

令我們非常高興的是，正如我們根據在 PN 領域的經驗所預期的那樣，支付方實際上理解並欣賞該產品帶來的價值。顯然，這種疾病具有高度分化性，而且實際上是致命的，病情發展迅速。支付者和醫生都非常清楚，這種疾病需要及早有效治療。

And what we're seeing is not only within actually '26 but -- sorry, but '25 but also '26. Policies are being negotiated, and it's -- they're almost final. And we're seeing a very similar dynamic that we had anticipated early in the launch.

我們看到的情況不僅發生在 2026 年，而且——抱歉，是 2025 年，但也發生在 2026 年。政策正在協商中，而且──幾乎已經定稿。我們看到的情況與我們在產品發布初期預期的情況非常相似。

Thanks, Tolga. That's great.

謝謝你，托爾加。那太棒了。

Maurice Raycroft, Jefferies.

莫里斯‧雷克羅夫特，傑富瑞集團。

Wondering if you can comment more on just the inventory demand number for third quarter and how to think about that for fourth quarter, along with gross to net and can you walk us through your expectations for fourth quarter revenues in the EU and how to think about the ramp up there?

想請您詳細談談第三季的庫存需求數據，以及第四季該如何看待這個問題，還有毛利與淨利的比較。另外，您能否詳細介紹一下您對第四季度歐盟地區收入的預期，以及如何看待該地區的成長？

Jeff, I think that's one for you.

傑夫，我覺得這事該你來做。

Yes. I'll take the question on inventory and gross to net in the third quarter, very similar dynamics to what we saw in the second quarter. From an inventory standpoint, days on hand stayed pretty constant -- for the quarter, but there was growth in inventory in the channel, and that's because of the way the day on -- of inventory is calculated. It's based on demand. And given the ramping demand, that's what created additional inventory going into the channel for the quarter.

是的。我將回答有關第三季庫存和毛利與淨利的問題，其動態與第二季非常相似。從庫存角度來看，本季庫存週轉天數基本上保持不變，但通路庫存有所成長，這是因為庫存週轉天數的計算方式。這是根據需求而定的。鑑於需求不斷增長，這導致了本季通路庫存的增加。

That was more than offset in the quarter by an increase in gross to net. Tolga mentioned ONPATTRO. That was the biggest driver of the increase in gross to net between Q2 and Q3, where we see gross to net for the TTR franchise for the year continues to be mid-single-digit price decline on a net price basis on a year-over-year basis.

本季毛利淨利的成長完全抵消了這一影響。托爾加提到了 ONPATTRO。這是第二季到第三季毛利淨利成長的最大驅動因素，我們看到 TTR 特許經營權的毛利淨利全年繼續出現個位數中段價格年減。

I think that Maury, maybe if you could repeat the other question about Europe and maybe -- today want to take that one. In terms of expectations for Q4, I think he was asking about. Is that right, Maury?

莫里，我想，也許你可以重複關於歐洲的另一個問題，也許──今天我想談談這個問題。關於第四季的預期，我想他問的是這個。莫里，是這樣嗎？

Yes, that's right. And just how to think about the ramp up in Europe as well.

是的，沒錯。以及歐洲市場該如何看待產能提升的問題。

Right. So I think the -- if I were to think in a greater scheme of things, the contribution of ex US market is going to remain relatively modest, especially for fourth quarter, given that we only have really two markets that's going to be -- that's right now available. Germany and Japan. In Germany, we're continuing to actually have final pricing discussions.

正確的。所以我認為——如果我從更宏觀的角度來看，除美國以外的市場貢獻將保持相對適中，尤其是在第四季度，因為我們目前只有兩個市場真正可用。德國和日本。在德國，我們仍在進行最終定價的討論。

So that's obviously going to be rather limited. In Japan, we're very pleased with the momentum that we built. But again, in the greater scheme of things, the contribution is going to be very modest.

所以這顯然會相當有限。在日本，我們對所取得的進展勢頭非常滿意。但從長遠來看，這筆貢獻將非常有限。

So ex US market is going to be mainly 2026, mid- to late 26 story. What I really like seeing is how we're actually maintaining our PN business. If you look at year over year, the growth now is 46% in ex US and TTR markets.

所以，除美國市場外，其他市場的發展主要將發生在 2026 年，也就是 2026 年中後期。我真正樂於看到的是我們如何切實地維持我們的PN業務。如果從同比來看，除美國和TTR市場外，目前的成長率為46%。

That suggests that -- and this is actually in the presence of a new competitor now. So look, I mean, I think just like what we've done in the US, in the PN markets, we are competing very effectively capturing majority of the first-line patients. And we've actually established a great ecosystem and these key centers of excellence in Europe really recognize the value of our treatment and the product profile. So I would expect more to come on that in '26.

這表明——而且現在實際上出現了一個新的競爭對手。所以你看，我的意思是，我認為就像我們在美國PN市場所做的那樣，我們正在非常有效地參與競爭，贏得了大多數一線患者的青睞。我們實際上已經建立了一個很棒的生態系統，歐洲的這些關鍵卓越中心真正認識到我們療法和產品特性的價值。所以我預計2026年會有更多相關消息公佈。

That's great, Phil. Look, I mean, I think as a company, we've built a really phenomenal R&D engine. And I think now we established a very robust commercial engine. So thanks to Tolga and his team with their achievements over the last quarter.

太好了，菲爾。你看，我的意思是，我認為作為一個公司，我們已經建立了一個非常出色的研發引擎。我認為我們現在已經建立了一個非常強大的商業引擎。所以，感謝托爾加和他的團隊在過去一個季度所取得的成就。

Jessica Fye, JPMorgan Chase.

潔西卡費伊，摩根大通。

Congrats on the quarter. I was curious if you could just elaborate on the approach you took to updating the TTR franchise guidance this time around in light of the fact that, as you said, we're still just two quarters into the cardiomyopathy launch?

恭喜你本季取得佳績。我想請您詳細說明一下，鑑於您所說的，我們目前才剛進入心肌病產品上市的兩個季度，您這次在更新 TTR 產品線指導意見時採取了哪些方法？

Yes. I'm happy to take that, Jess. We updated the guidance. So obviously, what we're really doing here is predicting what we're going to see in the fourth quarter because that's the only time point we've got left in the year relative to the guidance that we've just issued.

是的。我很樂意接受，傑西。我們更新了指南。顯然，我們現在所做的，是預測第四季度的情況，因為相對於我們剛剛發布的指導意見而言，這是我們今年唯一剩下的時間點。

And if you look at the guidance, it's roughly estimating total TTR global revenue of $850 million to $900 million in the fourth quarter, which would reflect $125 million to $175 million of quarter-on-quarter growth on that range.

如果你看一下業績指引，它大致預期 TTR 第四季的全球總營收為 8.5 億至 9 億美元，這意味著季增 1.25 億美元至 1.75 億美元。

The upper end of that range is very close to what we've delivered in both Q2 and Q3. And so I would say that's really how we've develop the guidance.

該範圍的上限與我們在第二季和第三季實現的數值非常接近。所以我覺得，這才是我們制定指導方針的真正方式。

We're continuing to learn. As Tolga said, we're two quarters in. I think our understanding of the business and the ability to forecast it is improving as we get more data points. But we're comfortable with the range, and I would think about the midpoint is the most likely outcome for Q4.

我們仍在不斷學習。正如托爾加所說，我們已經過了兩個季度了。我認為，隨著我們獲得更多數據點，我們對業務的理解和預測能力正在提高。但我們對這個範圍感到滿意，我認為第四季最有可能的結果會是中間值。

Luca Issi, RBC.

Luca Issi，RBC。

Great. Thanks so much. I think congrats on another fantastic quarter. Maybe Tolga, CMS is obviously proposing to cut reimbursement for (inaudible) I think, by 57% from $1,300 all the way down to $500. I guess what was your reaction to that news and maybe related, do you think that such efforts from CMS will remain insulated to just the diagnostic side of the equation?

偉大的。非常感謝。我認為恭喜你們又取得了一個非常棒的季度成績。或許托爾加，CMS顯然提議削減（聽不清楚）的報銷額，我認為是從1,300美元削減57%，一直削減到500美元。我想知道你對這個消息的反應是什麼？另外，你認為CMS的這些努力是否會只限於診斷方面？

Or you think that CMS will optimal look also on the therapeutic side of the equation, given obviously the cost therapeutics are much higher than the diagnostics side? And then maybe super quickly, can you just maybe talk about subpoena from the US Attorney General that you put in the press release?

或者您認為，考慮到治療費用顯然比診斷費用高得多，CMS（醫療保險和醫療補助服務中心）也會從治療方面考慮？然後，能否快速談談您在新聞稿中提到的美國司法部長傳票？

Well, look, why don't I take the subpoena question really quickly. And look, clearly, we intend to work with the US Attorney's office to produce the documents that have been requested by the subpoena and to understand, and address any potential concerns with respect to government price reporting. And of course, as you know, we don't generally comment on legal matters, but thank you for the question. And I'll hand it over to Tolga to take the remainder of your question.

好吧，那我就快速回答一下傳票問題吧。顯然，我們打算與美國檢察官辦公室合作，提供傳票要求的文件，並了解和解決與政府價格報告相關的任何潛在問題。當然，正如您所知，我們通常不會對法律問題發表評論，但感謝您的提問。接下來，我會把問題交給托爾加，請他來回答你剩下的問題。

Yes. So scans and how they are being currently reimbursed is obviously has been an important driver for the growth of this category. We actually anticipate more diagnosis and more scanning. We need to really fully understand how that reimbursement is actually going to play out.

是的。因此，掃描及其目前的報銷方式顯然是推動這一類別成長的重要因素。我們預計會有更多診斷和更多掃描。我們需要真正全面地了解這筆報銷款項究竟會如何發放。

We haven't really seen any anxiety or concerns in the health systems that we're engaging with. So we're obviously, again, staying in tune and I'm sure we'll be able to manage that as the policy becomes more clear.

我們尚未在我們接觸的醫療系統中看到任何焦慮或擔憂。所以，我們顯然會繼續密切關注事態發展，我相信隨著政策變得更加明朗，我們一定能夠應對自如。

Gena Wang, Barclays.

吉娜·王，巴克萊銀行。

Also congrats on the great quarter. So maybe just want to confirm I heard correct that the price for AMVUTTRA will be declined at the mid-single digit year over year in the US? And a related question is that once you launch your (inaudible) , in Europe, how should we think about price change in Europe? Should we expect a huge dip or largely align with the US?

也恭喜你們本季業績出色。所以，我只是想確認一下我是否理解正確，AMVUTTRA 在美國的價格將比去年同期下降個位數中段？還有一個相關的問題是，一旦你在歐洲推出你的（聽不清楚）產品，我們該如何看待歐洲的價格變動？我們應該預期出現大幅下跌，還是會與美國基本上保持一致？

And then second question is regarding the AMVUTTRA in ATTR cardiomyopathy in the US. Just wondering if you can share a little bit more color regarding the ratio between the first line versus second line. Are we talking about roughly 50-50 or second line is slightly higher?

第二個問題是關於美國 ATTR 心肌病變的 AMVUTTRA。我想問一下，您能否再詳細解釋一下第一行和第二行之間的比例關係？我們說的是大致五五開，還是第二條線略高一點？

So we got a number of questions here about price year on year in the US price and color on the first line, second line split. I think all of those are for you Tolga. Why don't you go ahead.

所以，我們收到了一些關於美國價格逐年變化的問題，以及第一行和第二行顏色的劃分。我覺得這些都是給你的，托爾加。為什麼不繼續呢？

I mean, look, Gena, as we had highlighted before, we would actually anticipate our net price to be gradually going down over time. And what you're seeing is perhaps some of those impacts and we'll continue to provide, obviously, what gross to net actually margins will look like over time.

我的意思是，吉娜，正如我們之前強調的那樣，我們預計我們的淨價實際上會隨著時間的推移而逐漸下降。而您現在看到的可能就是其中一些影響，我們當然會繼續提供毛利潤與淨利潤隨時間推移的實際變化。

But I wouldn't expect a serious or significant shift in that. Now when it comes to Europe, obviously, those negotiations are continuing. And what we're making sure is that we are taking into account MFN and a number of other dynamics. And we'll obviously be able to provide a much more broader outlook in terms of how the volume and price is going to play out in the outer years.

但我預計這種情況不會發生重大或顯著的變化。至於歐洲方面，顯然，相關談判仍在持續。我們正在確保的是，我們考慮到了最惠國待遇和其他一些動態因素。顯然，我們將能夠對未來幾年銷量和價格的走勢提供更全面的展望。

As I said before, this is really going to be a mid- to late '26 story. And your other question is around remind me again, is ratio of first line and second line. Yes.

正如我之前所說，這真的會是 2026 年中後期發生的故事。你的另一個問題是關於提醒我一下，第一行和第二行的比例是多少。是的。

I mean, look, I think what we really like to see so far, what we've been seeing is, we are increasingly getting more competitive in first line, second line in terms of stabilizer that obviously is an existing patient pool that has actually started very early in the launch, but what we like seeing is after first month into the launch, we start seeing a much more balanced and broad uptake between first and second line. And we certainly expect that to continue as we actually increase our first-line presence in the outer quarters.

我的意思是，你看，我認為到目前為止我們真正樂於看到的是，我們在一線和二線穩定劑領域越來越有競爭力，這顯然是基於現有患者群體，他們實際上在產品上市初期就開始使用。但我們樂於看到的是，在上市第一個月之後，我們開始看到一線和二線的使用更加平衡和廣泛。我們當然希望隨著我們在外圍地區一線力量的不斷增強，這種情況能夠繼續下去。

Yes. And I'd just like to add how well the data from HELIOS-B are actually resonating with physicians. I mean, being -- cabin the first silence TTR with rapid knockdown of TTR resource. I think that's having an impact. I think the data that we continue to generate is important.

是的。我還要補充一點，HELIOS-B 的數據其實引起了醫生們的共鳴。我的意思是，成為－小屋第一個寂靜的TTR，TTR資源迅速被擊倒。我認為這正在產生影響。我認為我們持續產生的數據非常重要。

I mean, Pushkal touched on this in terms of 37% relative risk reduction in all-cause mortality and first CV events. I think Pushkal also touched on the multisystem nature of the disease with a reduction in GI events. That really is, I think, I think, a compelling additional data point for physicians.

我的意思是，Pushkal 曾提到，全因死亡率和首次心血管事件的相對風險降低了 37%。我認為普什卡爾也提到了這種疾病的多系統性，包括胃腸道事件的減少。我認為，這對醫生來說確實是一個很有說服力的額外數據點。

And of course, the quarterly regimen, I think, also resonates well where physicians can be sure that patients are actually going to receive their drug given the quarterly subcutaneous administration. So all in all, I think we feel really well positioned in this market.

當然，我認為每季給藥一次的方案也引起了醫生的共鳴，因為醫生可以確保患者確實會接受到藥物，這是透過每季一次的皮下注射來實現的。總而言之，我認為我們在這個市場中處於非常有利的地位。

Both for a growing position in first line as Tolga said, we're highly competitive here and obviously, the leading choice for patients who continue to progress on stabilizes. So we feel we've built some really good foundations here. Thank you for the question.

正如托爾加所說，我們既在不斷增長的一線地位方面具有很強的競爭力，而且顯然，對於病情持續穩定的患者來說，我們是首選。所以我覺得我們已經在這裡打下了非常好的基礎。謝謝你的提問。

So I think we're on to our -- just two more questions.

所以我想我們接下來──只剩下兩個問題了。

Ritu Baral, TD Cowen.

Ritu Baral，TD Cowen。

Just back to Europe, Tolga. Can you talk about what degree of commercial investment is needed in Europe to expand beyond the PN indication. We're trying to figure out how to balance that against any potential lower cost? And then just a very quick follow-up. As we think about that first line dynamics, how much does center type impact first-line use, basically, if they're in commercial hospital systems versus patient characteristics?

托爾加，我剛回到歐洲。您能否談談在歐洲需要多大程度的商業投資才能將適應症擴展到PN以外？我們正在努力弄清楚如何平衡這一點與任何潛在的更低成本之間的關係？然後還有一個非常簡短的後續問題。當我們思考第一線治療的動態時，中心類型（如果它們屬於商業醫院系統）與患者特徵相比，對第一線治療的使用有多大影響？

No, that's helpful. Thank you, Ritu. So here are a few points around how you should be thinking about Europe. So we actually have quite an effective team that has been able to establish a market leadership versus tafamidis in the polyneuropathy organization. And the main reason why that organization is so effective is because this is a category, particularly in Europe, is really managed by centers of excellence, perhaps maybe with the exception of Germany.

不，這很有幫助。謝謝你，麗圖。以下是關於你如何看待歐洲的一些要點。因此，我們實際上擁有一支非常有效率的團隊，能夠在多發性神經病變領域建立起相對於 tafamidis 的市場領導地位。該組織之所以如此高效，主要原因是這一類別，尤其是在歐洲，實際上是由卓越中心管理的，也許德國是個例外。

In most other centers, this is in countries. This is really managed by centers, albeit Italy or France, and some other major other European countries. We know in the UK, for instance, there is one single center national media center that manages that. So it does require in test collaboration and obviously, a scientific engagement.

在其他大多數中心，這種情況發生在國家。這實際上是由一些中心管理的，可能是義大利或法國，也可能是其他一些主要的歐洲國家。例如，我們知道在英國，有一個國家媒體中心負責管理媒體事務。因此，這確實需要測驗中的合作，顯然也需要科學的參與。

But in terms of the field activity, that's rather limited. And cardiomyopathy patients are actually mostly treated in these centers as well. So we wouldn't expect a significant expansion of our European businesses. Now when it comes to Japan, that market is a little more fragmented, so we do actually invest. We certainly play to win in that category, and we will obviously continue to invest what's necessary to make sure that the product profile is well understood and appreciated.

但就實地活動而言，這相當有限。心肌病變患者也大多在這些中心接受治療。因此，我們預計歐洲業務不會大幅擴張。至於日本市場，由於市場較為分散，所以我們確實會進行投資。我們當然會全力以赴爭取在這個領域取得勝利，而且我們顯然會繼續投入必要的資源，以確保產品特性得到充分理解和認可。

Thanks, Tolga. So one more question with our last question coming out.

謝謝你，托爾加。最後一個問題來了。

Cory Kasbah, Evercore.

Cory Kasbah，Evercore。

This is Adi on for Cory. The tafamidis trends show a clear NRx jump from fourth quarter to first quarter in both 2024 and 2025. Should we model a similar jump up for AMVUTTRA, thinking that is it because of IRA Part D modifications in the past year or normal seasonality?

這是Adi替Cory主持節目。tafamidis 的趨勢顯示，2024 年和 2025 年的 NRx 均從第四季到第一季出現顯著成長。我們是否應該對 AMVUTTRA 進行類似的建模，並思考這是由於過去一年 IRA Part D 的修改還是正常的季節性因素造成的？

Yes. So maybe I'll take your question more from a perspective of category growth and what you should be expecting. Look, first and foremost, it's obviously still early days. And only one company has reported so far in terms of their quarter-over-quarter dynamic.

是的。所以，或許我會從品類成長以及您應該期待什麼的角度來回答您的問題。首先，顯然現在還處於早期階段。目前只有一家公司公佈了季度環比業績。

But -- and we still like to see how Pfizer is going to report before we drove some firm conclusions about how that dynamic is working. But that said, everything that we're seeing, the category growth in ATTR-CM is accelerating.

但是——我們仍然想看看輝瑞公司將如何發布報告，然後再對這種動態如何運作得出一些確切的結論。但即便如此，我們所看到的一切，ATTR-CM 品類的成長正在加速。

And it's no surprise because we all know that this is an underdiagnosed and undertreated category, and there are a lot of patients are still waiting. And we've also seen this very much on (inaudible) neuropathy with just one product coming in on top of us, we've seen the category growing, accelerating a lot faster.

這不足為奇，因為我們都知道這是一個診斷不足、治療不足的疾病類別，還有很多患者仍在等待治療。我們也看到，在（聽不清楚）神經病變領域，光是一款產品上市，我們就看到該類別成長得更快、更迅速。

And the good news on polderopathy, we still remain actually the first-line market share leader. And within the expected category growth I would say we are exceptionally well positioned. As Yvonne and Pushkal mentioned, we are well differentiated in terms of our mechanism.

好消息是，在圩田病領域，我們仍然是市佔率領先的第一線企業。在預期的品類成長範圍內，我認為我們處於非常有利的地位。正如伊馮娜和普什卡爾所提到的，我們的機制具有強烈的差異化。

We obviously have the robust outcomes supplied by HELIOS-B and importantly, we are continuing to invest in the category, especially on real-world evidence and data generation across both clinical and real-world setting. So our evidence base is strengthening. That really positions us to become a market leader in this growing category.

我們顯然擁有 HELIOS-B 提供的可靠結果，更重要的是，我們正在繼續投資於該領域，尤其是在臨床和真實世界環境中的真實世界證據和數據生成方面。因此，我們的證據基礎正在不斷加強。這確實使我們有能力成為這個不斷成長的品類中的市場領導者。

Great. Well, I think that brings our call to a close. And I'd just like to thank everybody who's joined us today. Look, our execution this quarter commercially in respect to our pipeline, I think it really demonstrates the new unique trajectory we have at Alnylam to become a top-tier biotech company and we look forward to sharing with you additional updates as we embark on realizing this vision. So thank you, everybody, and have a great day.

偉大的。好了，我想我們的通話到此結束了。我還要感謝今天到場的每一位朋友。你看，就我們本季在產品線方面的商業執行情況而言，我認為這真正展現了Alnylam成為一流生物技術公司的獨特新發展軌跡，我們期待在實現這一願景的過程中與大家分享更多最新進展。謝謝大家，祝大家今天過得愉快。

Thank you. Ladies and gentlemen, this does indeed conclude your conference call for today. Once again, thank you for attending. And at this time, we do ask that you please disconnect your lines.

謝謝。女士們、先生們，今天的電話會議到此結束。再次感謝各位的出席。此時，請您斷開線路。