Alnylam Pharmaceuticals Inc (ALNY) 2025 Q4 法說會逐字稿

Good morning ladies and gentlemen, and welcome to the Alnylam Pharmaceuticals Q4 and full-year 2025 earnings conference call. (Operator Instructions) This call is being recorded on Thursday, February 12, 2026.

女士們、先生們，早安，歡迎參加 Alnylam Pharmaceuticals 2025 年第四季及全年業績電話會議。（操作員指示）本次通話於 2026 年 2 月 12 日星期四進行錄音。

I would now like to turn the conference over to Christine Akinc. Please go ahead.

現在我將把會議交給克里斯汀·阿金克主持。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. 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.

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。對於透過電話會議參與的各位，可以透過造訪我們網站投資者頁面的「活動」部分（investors.alnylam.com/events）來取得隨附的幻燈片。

During today's call, as outlined in slide 2, Yvonne will offer introductory remarks and provide some general context. Tolga will provide an update on our global commercial progress. Pushkal will review pipeline updates, clinical progress and upcoming milestones, and Jeff will review our financials and guidance before we open the call to your questions.

在今天的電話會議中，如幻燈片 2 所示，伊馮娜將作開場白並提供一些一般背景資訊。托爾加將介紹我們全球商業進展的最新情況。Pushkal 將回顧產品線更新、臨床進展和即將到來的里程碑，Jeff 將回顧我們的財務狀況和業績指引，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 purposes of the Safe Harbor provision under the Private Securities Litigation 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 as of any subsequent date. We specifically disclaim any obligations 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截至任何後續日期的觀點。我們特此聲明，我們不承擔更新此類聲明的任何義務。

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 possesses a truly unique profile in the biotech industry, underpinned by our established and sustainable innovation engine, coupled with commercial excellence, driving durable long-term growth. We're the leaders in RNAi therapeutics with a proven organic product engine and a reproducible and modular process for developing our medicines that has resulted in outsized historical success rates.

謝謝克里斯汀，也謝謝大家今天參加電話會議。Alnylam 在生技產業擁有真正獨特的地位，這得益於我們成熟且可持續的創新引擎，以及卓越的商業能力，從而推動了持久的長期成長。我們在 RNAi 療法領域處於領先地位，擁有成熟的有機產品引擎和可複製的模組化藥物開發流程，從而取得了超乎尋常的歷史成功率。

We also have a high-yielding pipeline with over 25 programs currently in active clinical development. And there are now six Alnylam invented medicines on the market that are collectively generating several billion dollars in annual revenues and treating hundreds of thousands of patients around the world. This broad execution across all areas of the business was clearly evident in 2025, which was a transformational year for Alnylam.

我們也擁有高產量的研發管線，目前有超過 25 個專案正在進行積極的臨床開發。目前，Alnylam 公司研發的六種藥物已上市，每年創造數十億美元的收入，並為世界各地數十萬名患者提供治療。2025 年，Alnylam 在各個業務領域都得到了廣泛的執行，這一年對 Alnylam 來說是具有變革意義的一年。

In terms of commercial and financial performance, we achieved a landmark approval of AMVUTTRA for ATTR cardiomyopathy and driven by the success of that launch, delivered nearly $3 billion in combined net product revenues, which was 81% growth compared to 2024. Importantly, we met or exceeded all of our ambitious Alnylam P5x25 goals. And with today's announcement, we can now officially declare that we have achieved GAAP profitability for the 2025 full-year and expect to sustain profitability going forward.

在商業和財務表現方面，我們獲得了 AMVUTTRA 用於治療 ATTR 心肌病變的里程碑式批准，並且在該產品成功上市的推動下，實現了近 30 億美元的合併淨產品收入，比 2024 年增長了 81%。重要的是，我們達到或超越了我們雄心勃勃的 Alnylam P5x25 目標。隨著今天的公告，我們現在可以正式宣布，我們已經實現了 2025 年全年的 GAAP 盈利，並預計未來將保持盈利。

On the pipeline and platform side, in 2025, we initiated three Phase III studies and expanded our clinical pipeline with four proprietary CTAs in addition to the five that were filed by our partners. We also developed and launched a potential best-in-class enzymatic ligation based RNAi manufacturing platform called siRELIS. We believe this platform will enable us to greatly expand our capacity and bring RNAi therapeutics to more patients around the world while reducing the cost of goods.

在研發管線和平台方面，2025 年，我們啟動了三項 III 期研究，並擴大了我們的臨床研發管線，除了合作夥伴提交的五項 CTA 外，我們還擁有四項自主研發的 CTA。我們還開發並推出了一種潛在的同類最佳的基於酶連接的 RNAi 生產平台，稱為 siRELIS。我們相信，該平台將使我們能夠大幅擴大產能，並將 RNAi 療法帶給世界各地更多的患者，同時降低產品成本。

While 2025 was a defining year for the company, we're now focused firmly on the future, harnessing our success to accelerate innovation and scale impact. To that end, we're excited to have recently shared our new set of five-year goals on Alnylam 2030. And these goals rest upon three strategic pillars, starting with achieving global TTR leadership while building a durable TTR franchise. We aspire to lead this market in revenue by 2030 and across the period and to launch nucresiran in 2028 for polyneuropathy and 2030 for cardiomyopathy.

雖然 2025 年是公司具有決定性意義的一年，但我們現在將目光堅定地投向未來，利用我們的成功來加速創新並擴大影響力。為此，我們很高興最近在 Alnylam 2030 上分享了我們新的五年目標。這些目標建立在三大策略支柱之上，首先是實現全球 TTR 領導地位，同時建立持久的 TTR 特許經營權。我們力爭在 2030 年及以後的時間裡引領該市場的收入，並於 2028 年推出用於治療多發性神經病變的 nucresiran，於 2030 年推出用於治療心肌病變的 nucresiran。

The next pillar is growing through sustainable innovation where we plan to deliver two or more transformative medicines beyond TTR that have blockbuster potential. We also aspire to achieve delivery of RNAi to 10 tissue types and have a pipeline of over 40 clinical programs by the end of 2030. The high-yielding platform and outsized historical probability of success, combined with our rigorous and disciplined approach to portfolio management. We believe this is the right place to focus our efforts and resources, and we expect to invest approximately 30% of our revenues in non-GAAP R&D across the period to accelerate organic internal innovation and selectively access external innovation.

下一個支柱是透過永續創新實現成長，我們計劃在 TTR 之外推出兩種或更多具有重磅潛力的變革性藥物。我們也力爭在 2030 年底前實現 RNAi 向 10 種組織類型的遞送，並擁有超過 40 個臨床項目。此平台收益豐厚，歷史成功機率極高，再加上我們嚴謹自律的投資組合管理方法。我們相信這是我們應該集中精力和資源的地方，我們預計在此期間將把大約 30% 的收入投入到非 GAAP 研發中，以加速內部有機創新並有選擇地獲取外部創新。

Given our expertise and leadership in this space, we believe this is a prudent allocation of capital that has the potential to deliver significant growth in the future.

鑑於我們在該領域的專業知識和領導地位，我們認為這是一項審慎的資本配置，未來有可能帶來顯著成長。

The final pillar of our 2030 goals is scaling with discipline and agility to drive sustained profitable growth. This includes striving to achieve over 25% revenue CAGR through the end of 2030 and to deliver a non-GAAP operating margin of approximately 30% across the period. It's important to note that this operating margin goal is only through 2030, which is the year we aim to achieve regulatory approval for nucresiran in ATTR cardiomyopathy.

我們2030年目標的最後一個支柱是，透過自律和敏捷的方式擴大規模，以推動持續獲利成長。這包括力爭到 2030 年底實現超過 25% 的收入複合年增長率，並在此期間實現約 30% 的非 GAAP 營業利潤率。值得注意的是，這個營業利潤率目標僅持續到 2030 年，因為我們計劃在 2030 年獲得 nucresiran 在 ATTR 心肌病變治療中的監管批准。

And if the nucresiran is successful in demonstrating the best-in-class profile that we expect, we believe it would drive swift patient uptake and given the lack of any royalty obligation for nucresiran potentially drive our operating margins to the mid-40s post 2030. Through these goals, I hope you can appreciate that we're building on Alnylam for the future, delivering continued long-term growth, underpinned primarily by our RNAi innovation platform.

如果 nucresiran 能夠成功展現出我們預期的最佳療效，我們相信它將迅速獲得患者的認可，並且鑑於 nucresiran 沒有特許權使用費義務，它有可能在 2030 年後將我們的營業利潤率提高到 40% 左右。透過這些目標，我希望您能理解我們正在為 Alnylam 的未來發展奠定基礎，實現持續的長期成長，而這主要得益於我們的 RNAi 創新平台。

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. Q4 represented another quarter of strong growth for Alnylam. We delivered $995 million in combined net product revenues representing 121% growth year-over-year and 17% growth versus prior quarter. While our TTR franchise remains the primary growth engine, we're also seeing continued momentum in our rare disease business.

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。Alnylam第四季再次實現了強勁成長。我們實現了 9.95 億美元的合併淨產品收入，年增 121%，比上一季成長 17%。雖然我們的 TTR 特許經營業務仍然是主要的成長引擎，但我們也看到罕見疾病業務持續保持成長勢頭。

Let me start there. Our rare disease portfolio continues to deliver meaningful impact for patients and consistent performance for our business. In Q4, our rare franchise generated $136 million in net revenue, up 26% versus the same period last year, driven by increased patient demand and favorable order timing in partner markets. As a result, GIVLAARI and Oxlumo together became a $0.5 billion franchise in 2025, reflecting continued growth, more than five years post launch.

我就從這裡開始吧。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持續的績效成長。第四季度，我們的稀有特許經營業務創造了 1.36 億美元的淨收入，比去年同期增長了 26%，這主要得益於患者需求的增加以及合作夥伴市場訂單時機的有利性。因此，GIVLAARI 和 Oxlumo 合併後，在 2025 年成為一家價值 5 億美元的特許經營公司，這反映了在推出五年多後持續成長的態勢。

With that, let's turn to the TTR highlights. Q4 was another robust quarter for our TTR franchise, continuing the strong launch trajectory we saw in Q2 and Q3. Global TTR net revenues reached $858 million, up 18% versus the prior quarter and representing 151% growth year-over-year. In the US, net revenues for our TTR franchise grew 20% compared with Q3, '25 versus 222% versus Q4 2024. The quarter-over-quarter growth was primarily driven by a continued increase in US patient demand, partially offset by an increase in gross net deductions and an unfavorable inventory channel impact.

接下來，讓我們來看看TTR的精彩亮點。第四季度，我們的 TTR 系列產品又迎來了一個強勁的季度，延續了第二季和第三季強勁的上市勢頭。全球 TTR 淨收入達 8.58 億美元，比上一季成長 18%，年增 151%。在美國，我們的 TTR 特許經營權的淨收入與 2025 年第三季相比增長了 20%，與 2024 年第四季相比增長了 222%。季度環比成長主要得益於美國患者需求的持續成長，但部分被毛淨扣除額的增加和不利的庫存管道影響所抵消。

Outside the US, revenues grew 13% versus the prior quarter and 47% year-over-year, underscoring continued global momentum. We continue to be very pleased with the early signs in Japan, roughly six months into the CM launch as we continue to track in line with leading launch analogs in the industry. In Germany, we recently aligned pricing for AMVUTTRA for the ATTR-CM opportunity, reflecting the significant larger prevalence of the CM indication relative to polyneuropathy indication.

在美國以外，營收較上一季成長 13%，年成長 47%，凸顯了全球業務的持續成長動能。我們對日本市場的早期跡象感到非常滿意，CM 上市大約六個月後，我們繼續保持著與業內領先的上市同類產品一致的進展。在德國，我們最近調整了 AMVUTTRA 在 ATTR-CM 領域的定價，這反映了 CM 適應症相對於多發性神經病變適應症更為普遍。

As expected, this will create a modest near-term impact on total TTR revenue in Q1. But importantly, it positions us to compete effectively and participate in a substantially larger CM market in Germany.

正如預期的那樣，這將對第一季 TTR 總收入產生適度的短期影響。但更重要的是，這使我們能夠有效地參與德國規模更大的內容管理市場。

As we have previously mentioned, we anticipate launching AMVUTTRA for ATTR cardiomyopathy in additional international markets throughout 2026 following the completion of local pricing and reimbursement reviews. As we continue to launch across ex-US markets, we are building global momentum that we expect to carry through 2026 and beyond.

正如我們之前提到的，在完成當地定價和報銷審查後，我們預計將在 2026 年在更多國際市場推出用於治療 ATTR 心肌病變的 AMVUTTRA。隨著我們繼續在美國以外的市場推出產品，我們正在建立全球發展勢頭，我們預計這種勢頭將持續到 2026 年及以後。

Finally, our international performance reflects the continued strength of our hereditary ATTR polyneuropathy legacy business, which remains robust despite competition. Broader engagement in the category is expanding awareness and diagnosis, ultimately benefiting patients and reinforcing Alnylam's leadership role in shaping the field.

最後，我們的國際業績反映了我們遺傳性 ATTR 多發性神經病傳統業務的持續強勁，儘管面臨競爭，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。

Now let's turn to the US ATTR-CM specific dynamics. Looking back on 2025, our confidence in the size growth and continued underpenetration of the ATTR-CM category has been reinforced. Despite approximately 40% volume CAGR over the past six years, the majority of patients with ATTR cardiomyopathy remain untreated. Against that backdrop, we are highly encouraged by AMVUTTRA's early momentum. In its first few quarters, performance relative to relevant specialty analogs supports the potential for a breakout launch, reflecting strong customer demand, the value of our AMVUTTRA's differentiated profile and disciplined commercial execution.

現在讓我們來看看美國 ATTR-CM 的具體動態。展望 2025 年，我們對 ATTR-CM 類別規模成長和持續滲透不足的信心得到了加強。儘管過去六年銷量複合年增長率約為 40%，但大多數 ATTR 心肌病變患者仍未接受治療。在此背景下，我們對 AMVUTTRA 的早期發展動能感到非常鼓舞。在上市的最初幾個季度，相對於相關專業同類產品的表現支持了其突破性上市的潛力，這反映了強勁的客戶需求、AMVUTTRA 的差異化特性和嚴謹的商業執行的價值。

When we look at the early launch data, what's most encouraging is not just the pace of uptake, but where AMVUTTRA is being used and why? First, AMVUTTRA is rapidly establishing itself as an important choice in new treatment starts. By just the second quarter post launch, AMVUTTRA approached parity with tafamidis in share of new starts based on available estimates. While these available data will continue to evolve, the early signal is clear. prescribing dynamics in ATTR-CM are shifting.

當我們查看早期發布數據時，最令人鼓舞的不僅是推廣速度，還有 AMVUTTRA 的使用地點和原因？首先，AMVUTTRA 正在迅速確立其在新治療方案中的重要選擇地位。根據現有估計，AMVUTTRA 在推出後的第二個季度，其新開工量份額就已接近 tafamidis。雖然現有數據還會不斷更新，但早期訊號很明確：ATTR-CM 的處方動態正在改變。

Second, we're gaining traction in first-line patients, establishing AMVUTTRA as a first-line option remains our strategic priority, and we're making meaningful progress. In parallel, AMVUTTRA has quickly become the preferred option for stabilizer and progress their patients consistent with its differentiated and orthogonal mechanism of action.

其次，我們在一線患者中取得了進展，將 AMVUTTRA 確立為第一線治療方案仍然是我們的策略重點，並且我們正在取得實質進展。同時，AMVUTTRA 憑藉其差異化和正交的作用機制，迅速成為穩定和改善患者病情的首選方案。

Third, this momentum is underpinned by broad and durable access. Following completion of our '26 payer policy discussion, we can look ahead with increased confidence to even broader patient access for AMVUTTRA in 2026 versus last year.

第三，這種勢頭得益於廣泛而持久的普及。在完成 2026 年支付方政策討論後，我們可以更有信心地展望 2026 年 AMVUTTRA 將為更多患者帶來福音，比去年更加廣泛。

Over 90% of payers now provide first-line coverage with the large majority of patients able to initiate treatment without step-through requirements. Most patients incur zero out-of-pocket costs and approximately 90% can access treatment within 10 miles of their home, supported by a broad, well-established network sites of care.

超過 90% 的支付方現在提供第一線保險，絕大多數患者無需經過其他治療階段即可開始治療。大多數患者無需自付費用，約 90% 的患者可以在離家 10 英里範圍內獲得治療，這得益於廣泛、完善的醫療服務網絡。

As we enter '26, we remain clear-eyed about where we are. The ATTR-CM launch is still in its early stages, just three quarters in, and there is important work ahead. At the same time, we have established the foundations for durable growth underpinned by a strong value proposition, broad access and steadily increasing customer demand.

進入2026年，我們依然清醒地認識到我們所處的位置。ATTR-CM 發射仍處於早期階段，目前僅進行了四分之三，未來還有許多重要工作要做。同時，我們憑藉著強大的價值主張、廣泛的市場准入和不斷增長的客戶需求，為永續成長奠定了基礎。

Looking forward, we see meaningful opportunity to further expand the category by improving diagnosis and treatment rates. And we are investing accordingly through targeted efforts in education and awareness, evidence generation and diagnosis enablement to ensure sustainable long-term impact for patients. We look forward to sharing more details at our upcoming investor webinar where we will mark the one-year anniversary of AMVUTTRA's US-FDA approval for ATTR cardiomyopathy on March 24, 2026, and highlight our progress for patients and the long-term growth and durability of our TTR franchise.

展望未來，我們看到了透過提高診斷和治療率來進一步擴大該類別的重要機會。我們正在透過有針對性的教育和宣傳、證據產生和診斷支持工作進行相應的投資，以確保對患者產生可持續的長期影響。我們期待在即將舉行的投資者網路研討會上分享更多細節，屆時我們將慶祝 AMVUTTRA 於 2026 年 3 月 24 日獲得美國 FDA 批准用於治療 ATTR 心肌病一周年，並重點介紹我們在患者方面取得的進展以及我們 TTR 產品線的長期增長和持久性。

With that, I'll hand over to Pushkal.

接下來，我將把麥克風交給普什卡爾。

Thank you, Tolga, and good morning, everyone. As Yvonne highlighted earlier, 2025 was indeed a year of substantial pipeline progress and platform innovation for Alnylam. First, we initiated three Phase III studies in 2025. Zenith is our event-driven cardiovascular outcomes trial for zilebesiran in patients with uncontrolled hypertension at high CV risk. We aim to enroll approximately 11,000 patients and have successful plan to launch around 2030.

謝謝你，托爾加，大家早安。正如伊馮娜之前強調的那樣，2025 年對 Alnylam 來說確實是管道建設取得重大進展和平台創新的一年。首先，我們在 2025 年啟動了三項 III 期研究。Zenith 是我們針對高心血管風險的未控制高血壓患者所進行的以事件驅動的心血管結局試驗，旨在評估齊來貝西蘭的療效。我們的目標是招募約 11,000 名患者，並計劃在 2030 年左右成功啟動。

Triton-CM is our event-driven outcome troughed for nucresiran in ATTR-CM. Approximately 1,200 patients will be enrolled in this study with launch also expected in 2030, if successful. And Triton-PN is an open-label study of nucresiran in approximately 125 patients with hereditary ATTR polyneuropathy, if successful approval in this indication is expected in 2028.

Triton-CM 是我們針對 ATTR-CM 中 nucresiran 的事件驅動結果谷值。這項研究將招募約 1200 名患者，如果成功，預計也將在 2030 年啟動。Triton-PN 是一項針對約 125 名遺傳性 ATTR 多發性神經病變患者的開放標籤研究，旨在評估 nucresiran 的療效。如果 nucresiran 能在 2028 年成功獲準用於該適應症，則將進行這項研究。

We also expanded our clinical pipeline, taking four new Alnylam-led programs into the clinic, ALN-2232, our first RNAi therapeutic directed to an adipose target, ACVR1C, with the potential to lead to durable weight loss, particularly reduction in visceral fat that is associated with poor cardio-metabolic health; ALN-5288, carding MAPT, or tau, for Alzheimer's disease and other rare tauopathies and two new programs for which we are not yet disclosing details to two competitive reasons, ALN-4285 and ALN-4915.

我們還擴大了臨床研發管線，將四個由 Alnylam 主導的新項目推進到臨床階段：ALN-2232，我們首個針對脂肪組織靶點 ACVR1C 的 RNAi 療法，有望實現持久的體重減輕，特別是減少與心血管代謝健康不良相關的內臟脂肪；ALN-5288，靶向 MAPT（即 tau 蛋白），用於治療阿茲海默症和其他罕見的 tau 蛋白，靶向 MAPT）蛋白質疾病；以及兩個新項目，出於競爭原因，我們尚未披露其細節，分別是 ALN-4285 和 ALN-4915。

Our partnerships also continue to generate progress for five new partner-led programs entering the clinic in 2025 across a range of indications with significant unmet need. We're also excited for our partners at Regeneron. We remain on track to submit a US regulatory application in the first quarter for cemdisiran in generalized myasthenia gravis with potential approval anticipated later this year or early 2027.

我們的合作關係也持續推動五個新的合作夥伴主導計畫於 2025 年進入臨床階段，這些計畫涵蓋一系列存在重大未滿足需求的適應症。我們也為我們的合作夥伴 Regeneron 感到興奮。我們仍按計劃於第一季度向美國監管機構提交 cemdisiran 用於治療全身性重症肌無力的申請，預計將於今年晚些時候或 2027 年初獲得批准。

And finally, as Yvonne mentioned, we also launched siRELIS, our proprietary enzymatic ligation manufacturing platform. As a result, we ended 2025 with a pipeline of over 25 clinical programs, spanning multiple therapeutic areas across rare specialty and prevalent indications, representing a tremendous opportunity for improving patient health and creating value in the years ahead.

最後，正如伊馮娜所提到的，我們也推出了 siRELIS，這是我們專有的酵素連結生產平台。因此，到 2025 年底，我們擁有超過 25 個臨床項目，涵蓋罕見疾病專科和常見疾病等多個治療領域，這為在未來幾年改善患者健康和創造價值提供了巨大的機會。

Among these many programs, there are several that represent the next wave of transformative near-term RNAi therapeutics from Alnylam each of which has multibillion dollar potential. In the cardiovascular metabolic space, we're excited about zilebesiran, targeting angiotensinogen with the aim of achieving continuous control of blood pressure with just two doses per year. For metabolic diseases, we see compelling opportunities to address substantial unmet medical need in gaps in treatment left by GLP-1s in both overweight obesity and type-2 diabetes.

在這些眾多項目中，有幾個代表了 Alnylam 公司下一波具有變革意義的近期 RNAi 療法，每個療法都具有數十億美元的潛力。在心血管代謝領域，我們對 zilebesiran 感到興奮，它以血管緊張素原為靶點，旨在透過每年兩次給藥來實現對血壓的持續控制。對於代謝性疾病，我們看到了令人振奮的機會，可以解決 GLP-1 在超重肥胖和 2 型糖尿病治療方面留下的巨大未滿足的醫療需求空白。

And in neuroscience, Mivelsiran targets amyloid precursor protein for the potential treatment of cerebral amyloid angiopathy and Alzheimer's disease. APP is a genetically validated target for both of these diseases and CAA, in particular, represents a blue ocean opportunity. ALN-HTT02 employs a unique exon 1 targeting approach with the potential to address Huntington's disease, a disease with no approved therapies through deep and widespread lowering of the Huntington protein in the brain.

在神經科學領域，Mivelsiran 靶向澱粉樣前體蛋白，有望用於治療腦澱粉樣血管病變和阿茲海默症。APP 是這兩種疾病的基因驗證標靶，特別是 CAA，代表著一片廣闊的市場機會。ALN-HTT02 採用獨特的靶向外顯子 1 的方法，預計將透過深度和廣泛降低大腦中的亨廷頓蛋白來治療亨廷頓氏症，目前尚無核准的治療方法。

And in hematology, ALN-6400 offers an exciting opportunity for a pipeline and a product, targeting plasminogen to address a wide range of bleeding disorders with a unique approach that has the potential to reduce bleeding without increasing the risk of thrombosis. Our first indication is hereditary hemorrhagic telangiectasia which affects approximately 70,000 patients in the United States.

在血液學領域，ALN-6400 為研發管線和產品提供了一個令人興奮的機會，它以纖溶酶原為靶點，採用獨特的方法治療各種出血性疾病，有可能在不增加血栓形成風險的情況下減少出血。我們首先發現的疾病是遺傳性出血性毛細血管擴張症，這種疾病在美國約有 7 萬名患者。

We'll share important updates across many of these programs over the year, as outlined in our 2026 pipeline goals. In the first half of the year, we plan to complete enrollment in the CAPRICORN 1 Phase II trial of Mivelsiran in patients with CAA and initiate 3 Phase II trials. The first of these has already been achieved, which is a Phase II study of ALN-4324 for patients with type-2 diabetes. The study is now actively enrolling patients, one for Mivelsiran in patients with Alzheimer's disease and another for ALN-6400 in a second bleeding disorder.

我們將在今年分享這些項目中許多項目的最新進展，正如我們在 2026 年發展目標中所概述的那樣。今年上半年，我們計劃完成 CAPRICORN 1 II 期試驗中 Mivelsiran 治療 CAA 患者的入組工作，並啟動 3 項 II 期試驗。第一個目標已經實現，即針對 2 型糖尿病患者的 ALN-4324 的 II 期研究。目前研究正在積極招募患者，一項研究針對阿茲海默症患者使用 Mivelsiran，另一項研究則針對第二種出血性疾病患者使用 ALN-6400。

Importantly, we expect to have clinical derisking data this year on several of the programs I just mentioned. Specifically, we expect to share Phase I and II results from the ALN-6400 program and Phase I data on both our Huntington's and ACVR1C programs in the second half of the year.

重要的是，我們預計今年將獲得我剛才提到的幾個項目的臨床風險降低數據。具體來說，我們預計將在今年下半年分享 ALN-6400 計畫的第一階段和第二階段結果，以及我們亨廷頓舞蹈症和 ACVR1C 計畫的第一階段數據。

And with that, let me now turn it over to Jeff to review our financial results and 2026 guidance. 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 2026 年的業績展望。傑夫？

Thanks, Pushkal, and good morning, everyone. I'm pleased to be presenting a summary of Alnylam's full year 2025 financial results and providing our comprehensive financial guidance for 2026. Let's begin with a summary of our P&L results for the full year. Total global net product revenues for 2025 were nearly $3 billion or 81% growth versus 2024, driven by a more than doubling of revenue in our TTR franchise primarily from the strong performance in the US following our Q2 launch of AMVUTTRA and ATTR cardiomyopathy. These full year results were more than $800 million above the original 2025 product sales guidance we provided last year, a testament to the strength of our ATTR-CM launch performance.

謝謝普什卡爾，大家早安。我很高興向大家介紹 Alnylam 2025 年全年財務表現概要，並提供我們對 2026 年的全面財務指導。讓我們先來總結一下我們全年的損益情況。2025 年全球淨產品總收入接近 30 億美元，比 2024 年增長 81%，這主要得益於 TTR 產品線收入翻了一番以上，而這主要得益於我們在第二季度推出 AMVUTTRA 和 ATTR 心肌病變後在美國的強勁表現。這些全年業績比我們去年提供的 2025 年產品銷售指引高出 8 億美元以上，證明了我們 ATTR-CM 上市表現的強勁。

For the full year, collaboration revenue was $553 million or 8% growth compared with 2024 and included a $300 million development milestone in Q3 associated with the dosing of the first patient in our Zenith Phase III cardiovascular outcomes trial for zilebesiran. Royalty revenue for the full year was $174 million, representing a 90% increase compared with last year, driven by higher LEQVIO sales from Novartis.

全年合作收入為 5.53 億美元，比 2024 年增長 8%，其中包括第三季度 3 億美元的開發里程碑，該里程碑與我們在 Zenith III 期心血管結果試驗中對 zilebesiran 的首例患者進行給藥有關。全年特許權使用費收入為 1.74 億美元，比上年成長 90%，主要得益於諾華公司 LEQVIO 銷售額的成長。

Gross margin on product sales was 77% for the full year representing a 4% decrease compared with 2024. The decrease in margin was primarily driven by increased royalties on AMVUTTRA as higher revenues in 2025 resulted in an increase in the average royalty rate payable to Sanofi compared with the prior year. Our non-GAAP R&D expenses of approximately $1.2 billion increased 17% compared to last year primarily driven by costs associated with the initiation of three Phase III clinical studies, including the Zenith Phase III cardiovascular outcomes trial for zilebesiran and the TRITON-CM and PN studies for nucresiran.

全年產品銷售毛利率為 77%，較 2024 年下降 4%。利潤率下降的主要原因是 AMVUTTRA 的特許權使用費增加，因為 2025 年更高的收入導致支付給賽諾菲的平均特許權使用費率比上一年增加。我們的非GAAP研發費用約為12億美元，比去年增長了17%，主要原因是啟動了三項III期臨床研究的相關成本，包括針對齊來貝西蘭的Zenith III期心血管結果試驗以及針對諾克雷西蘭的TRITON-CM和PN研究。

Non-GAAP SG&A expenses of approximately $1 billion increased 22% compared to last year, primarily driven by increased investments in support of the AMVUTTRA ATTR-CM launch in the US. We achieved full year non-GAAP operating income of $850 million, representing a $755 million increase compared with last year, driven primarily by the strong top line results that I previously highlighted.

非GAAP SG&A費用約為10億美元，比去年增長22%，主要原因是為支持AMVUTTRA ATTR-CM在美國的推出而增加了投資。我們全年非GAAP營業收入達到8.5億美元，比去年增加了7.55億美元，這主要得益於我之前重點提到的強勁的營收業績。

I'm also pleased to share today that we achieved profitability on both a GAAP and non-GAAP net income basis, both in the fourth quarter and for the full year 2025 and more than delivering on our P5x25 non-GAAP profitability goal. I'd like to take a moment to thank the Alnylam employees who made this milestone possible through their active engagement and scaling our business with discipline over the past five years.

今天我很高興地宣布，我們在 2025 年第四季度和全年都實現了 GAAP 和非 GAAP 淨利潤的盈利，並且超額完成了 P5x25 非 GAAP 盈利目標。我想藉此機會感謝 Alnylam 的員工，在過去的五年裡，他們積極參與並嚴謹地拓展業務，使這一里程碑成為可能。

Finally, we ended the year with cash, cash equivalents and marketable securities of $2.9 billion compared with $2.7 billion at the end of 2024. The primary drivers of the $200 million increase in cash during the year include improved operating performance and proceeds from the exercise of stock options, partially offset by net proceeds utilized during our convertible refinancing in Q3.

最後，到年底，我們的現金、現金等價物和有價證券總額為 29 億美元，而 2024 年底為 27 億美元。今年現金增加 2 億美元的主要原因是經營業績改善和行使股票選擇權所得，但部分被第三季可轉換再融資期間使用的淨收益所抵銷。

Now I'd like to turn to our financial guidance for 2026. Starting with net product revenues, we are reiterating the combined net product revenue guidance for AMVUTTRA, ONPATTRO, GIVLAARI and OXLUMO that we communicated in our JPMorgan press release dated January 11, 2026. We anticipate combined net product sales for our four commercial products will be within a range of $4.9 billion to $5.3 billion, representing combined full year growth compared to 2025 of 71% at the midpoint of the guidance range or more than $2.1 billion in growth.

現在我想談談我們對 2026 年的財務展望。首先，就淨產品收入而言，我們重申我們在 2026 年 1 月 11 日摩根大通新聞稿中公佈的 AMVUTTRA、ONPATTRO、GIVLAARI 和 OXLUMO 的合併淨產品收入預期。我們預計四款商業產品的合併淨銷售額將在 49 億美元至 53 億美元之間，與 2025 年相比，全年合併成長率將達到 71%（以指導範圍的中點計算），即成長超過 21 億美元。

On a franchise level, the guidance is broken down as follows: Total Rare, $500 million to $600 million, representing full year growth compared to 2025 of 10% at the midpoint of the guidance range. Total TTR, $4.4 billion to $4.7 billion representing full year growth compared to last year of 83% at the midpoint of the guidance range. As Tolga noted in his prior comments, it's still early days in the ATTR-CM launch but we are pleased with our initial momentum and the strong fundamentals which support the long-term growth potential of our TTR franchise.

從特許經營層面來看，指導意見細分如下：稀有產品總收入為 5 億美元至 6 億美元，與 2025 年相比，全年成長率為 10%（指引範圍的中點）。總 TTR 為 44 億美元至 47 億美元，與去年相比，全年成長率為 83%（以指導範圍的中點計算）。正如 Tolga 在他之前的評論中指出的那樣，ATTR-CM 的推出還處於早期階段，但我們對目前的勢頭和強大的基本面感到滿意，這支撐了我們 TTR 特許經營權的長期增長潛力。

As we highlighted at the JPMorgan conference, the 2026 TTR product sales guidance is underpinned by three key assumptions: First, we anticipate US TTR category growth will remain brisk and consistent with prior years. Second, in the US, we continue to expect a modest decrease in net price as our CM business continues to scale. Specifically, we forecast a mid-single-digit net price decrease for AMVUTTRA in 2026. Third, given the impact on our polyneuropathy business associated with lower CM launch pricing in international markets, we expect international TTR revenue dollar growth in 2026 will be consistent with 2025.

正如我們在摩根大通會議上所強調的那樣，2026 年 TTR 產品銷售指導基於三個關鍵假設：首先，我們預計美國 TTR 類別的成長將保持強勁，並與往年保持一致。其次，在美國，隨著我們的CM業務不斷擴大規模，我們預期淨價將繼續小幅下降。具體而言，我們預測 AMVUTTRA 在 2026 年的淨價格將出現中等個位數的下降。第三，鑑於國際市場上較低的 CM 上市價格對我們的多發性神經病變業務的影響，我們預計 2026 年國際 TTR 收入美元成長將與 2025 年保持一致。

I'd also like to provide some color on Q1 phasing assumptions associated with our full-year TTR revenue guidance. For Q1, we expect considerably lower quarter-on-quarter TTR revenue growth compared with the $134 million of TTR growth that we delivered in Q4 '25. The lower growth expectation in Q1 is driven by a variety of factors, including the following:

我還想就我們全年 TTR 收入預期相關的第一季階段性假設提供一些細節說明。對於第一季度，我們預計 TTR 營收季增將遠低於 2025 年第四季實現的 1.34 億美元 TTR 營收成長。第一季成長預期下調是由多種因素造成的，其中包括以下幾點：

First, unlike in Q4, when our international markets contributed $23 million in quarterly TTR revenue growth, we are expecting an approximate $25 million reduction in Q1 international revenues with the primary driver of the decrease attributable to our CM launch in Germany where our AMVUTTRA pricing was adjusted downward in late Q4, as Tolga previously mentioned. For the balance of the year, we expect our international markets will return to quarter-on-quarter growth as the impact of increasing volume outweighs reduced price.

首先，與第四季國際市場為季度 TTR 營收成長貢獻 2,300 萬美元不同，我們預計第一季國際營收將減少約 2,500 萬美元，下降的主要原因是我們在德國推出 CM 產品，正如 Tolga 之前提到的，我們在第四季末下調了 AMVUTTRA 的價格。今年剩餘時間裡，我們預計國際市場將恢復季度環比成長，因為銷售成長的影響將超過價格下降的影響。

Second, in the US, we expect more modest quarter-over-quarter TTR growth in Q1 compared with the USD111 million of quarterly growth achieved in Q4 due to fewer product shipping weeks in Q1 and the expected impact of annual insurance reauthorizations. Beyond Q1, we expect higher quarterly growth for the balance of the year in the US, and we remain confident in our full year TTR product sales guidance.

其次，在美國，我們預計第一季 TTR 環比成長將比第四季實現的 1.11 億美元環比成長更為溫和，這是由於第一季產品出貨週數減少以及年度保險重新授權的預期影響所致。第一季之後，我們預計今年剩餘時間美國市場的季度成長將更加強勁，我們對全年 TTR 產品銷售預期仍然充滿信心。

Now returning to our full year 2026 financial guidance. Our collaboration and royalty revenue guidance range is $400 million to $500 million, representing a decrease of 38% compared to 2025 at the midpoint of the guidance range driven by the onetime $300 million zilebesiran development milestone achieved in 2025 that I previously mentioned that will not recur this year. We expect the collaboration revenue associated with our partnerships with Roche and Regeneron as well as LEQVIO royalties from Novartis will drive the majority of our collaboration and royalty revenue this year.

現在回到我們2026年全年財務預期。我們的合作及特許權使用費收入預期範圍為 4 億美元至 5 億美元，與 2025 年預期範圍的中點相比，下降了 38%。這主要是由於我之前提到的 2025 年一次性 3 億美元的 zilebesiran 開發里程碑，而今年不會再次出現。我們預計，與羅氏和再生元合作帶來的合作收入以及諾華公司支付的 LEQVIO 專利使用費將成為我們今年合作和專利使用費收入的主要來源。

Our guidance for combined non-GAAP R&D and SG&A expense is a range between $2.7 billion and $2.8 billion, with the midpoint of the range representing 26% growth versus 2025. Growth drivers for R&D expense this year include increased investment in clinical studies including the continuation of pivotal Phase III studies for zilebesiran and nucresiran as well as early pipeline investment to deliver three to four new INDs and support expansion of delivery into new tissues. Growth in SG&A will primarily be driven by ongoing launch activities to support AMVUTTRA for ATTR-CM in the US and select international markets.

我們對非GAAP研發和銷售、管理及行政費用的綜合預期在27億美元至28億美元之間，其中價值代表比2025年增長26%。今年研發支出成長的驅動因素包括增加對臨床研究的投資，包括繼續進行 zilebesiran 和 nucresiran 的關鍵性 III 期研究，以及對早期研發管線的投資，以推出三到四個新的 IND 並支持將藥物遞送到新的組織。銷售、一般及行政費用的成長主要由持續進行的上市活動所推動，以支持 AMVUTTRA 在美國和部分國際市場推廣 ATTR-CM 產品。

Let me now turn it back to Christine to coordinate our Q&A session. Christine?

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. (Event Instructions)

謝謝你，傑夫。接線員，現在開始接受提問。（活動須知）

Thank you, ladies and gentlemen. We will now begin the question-and-answer session. (Operator Instructions)

謝謝各位女士、先生。現在開始問答環節。（操作說明）

I have Paul with Stifel.

我和保羅在史蒂費爾公司。

Hey, good morning. Can you hear me okay?

嘿，早安。你聽得清楚我說話嗎？

Yes, we can.

是的，我們可以。

Okay, great. Good morning. Thanks so much and appreciate you taking my question. I was wondering if you could just comment on what you're seeing so far in 2026 in terms of new patient adds and the mix of first line for vutrisiran versus tafamidis switches and how you see that evolving over the course of this year and what's assumed in guidance? Thank you.

好的，太好了。早安.非常感謝您回答我的問題。我想請您談談您對 2026 年新增患者數量、vutrisiran 與 tafamidis 一線治療方案轉換情況的看法，以及您認為這種情況在今年會如何發展，以及指南中有哪些假設？謝謝。

Yeah, that's a great question. I think it's important just to underscore how pleased we are with the AMVUTTRA launch so far. Coming out of the gate strong, we're building towards an analog beating launch and really building a long-term franchise that's incredibly important. And all the fundamentals are in place to drive continued AMVUTTRA growth, which I think is underscored by our 2026 guidance on our 2030 goals. But Tolga, maybe you will speak specifically to -- yes, I mean, how you're seeing the market.

是的，這是一個很好的問題。我認為有必要強調一下，我們對 AMVUTTRA 目前為止的發布情況非常滿意。我們開局強勁，正朝著超越模擬時代的發布目標邁進，並真正打造一個極其重要的長期品牌。所有基本要素都已到位，足以推動 AMVUTTRA 的持續成長，我認為我們在 2026 年對 20​​30 年目標的展望也印證了這一點。但是托爾加，也許你可以具體談談——是的，我的意思是，你是如何看待市場的。

Thanks, Yvonne. Look, as Yvonne highlighted, what really drives our confidence in reiterating the guidance is really is the fundamentals. If you think about it, we've actually improved our first-line access. We're clearly seeing a strengthening physician and patient preference and even more importantly, continued category growth with more patients entering the market. Those trends were in place heading into JPM and have continued to build, and that's why we remain confident in the year.

謝謝你，伊馮娜。正如伊馮娜所強調的那樣，真正讓我們有信心重申指導方針的是基本面。仔細想想，我們實際上已經改善了我們的第一線服務。我們明顯看到醫生和患者的偏好日益增強，更重要的是，隨著更多患者進入市場，該品類持續成長。這些趨勢在摩根大通成立之前就已經存在，並且一直在持續發展，這就是為什麼我們對今年仍然充滿信心。

Great. Thank you.

偉大的。謝謝。

Salveen with Goldman Sachs.

薩爾文就職於高盛。

Good morning. Thanks for taking my question. If I could just follow up on the confidence here and the guide for the year for the TTR franchise. Just speak to the the choppiness that we're seeing coming out of the scripts for the first quarter to date? And then how you think about the pricing dynamics as you look to a new potential market entry this year or next year as well as kind of the growth dynamics in Europe? Thank you.

早安.謝謝您回答我的問題。如果我能繼續跟進這裡的信心以及TTR系列的年度指南就好了。就第一季至今劇本中出現的不連貫性問題談談你的看法？那麼，當您考慮今年或明年進入新的潛在市場時，您會如何看待定價動態，以及歐洲的成長動態？謝謝。

Yeah. So let me take the pricing question first. We feel very well positioned from an access standpoint for this year. The large majority of patients have already first-line access without required petites and most patients are continuing to pay 0 out of pocket, partly supported by our value-based agreements and in fact, utilization within those agreements have been rather minimal to date.

是的。那麼，我先來回答定價問題。從准入角度來看，我們今年處於非常有利的地位。絕大多數患者已經無需支付任何費用即可獲得一線治療，而且大多數患者仍然無需自付任何費用，這部分得益於我們基於價值的協議，事實上，迄今為止，這些協議的使用率相當低。

In terms of on our pricing, our net price declined mid-single digits in '25 and our '26 guidance assumes a similar mid-single-digit decline. And that dynamic is fully integrated into our outlook. Now in terms of '27, it's obviously too soon for us to be able to provide specific guidance, but we felt really well positioned as we enter '26.

就定價而言，我們的淨價在 2025 年下降了中等個位數，我們對 2026 年的預期也假設會出現類似的中等個位數下降。這種動態已經完全融入我們的世界觀中。至於 2027 年，現在顯然還為時過早，我們無法提供具體的指導，但進入 2026 年，我們感覺自己已經做好了充分的準備。

Thanks, Tolga.

謝謝你，托爾加。

Kostas with Oppenheimer.

科斯塔斯和奧本海默。

Thanks for taking our question and congratulations on the strong year. A question on seasonality from us. Have you seen any seasonality during the fourth quarter, potentially patients who push the injection to the next quarter because of the holidays and whether this will be a tailwind for the first quarter of 2026. Thank you.

感謝您回答我們的問題，並祝賀您度過了碩果累累的一年。我們有一個關於季節性的問題。您是否觀察到第四季度存在季節性因素，例如患者可能因為假期而將注射推遲到下一季度，這是否會對 2026 年第一季產生正面影響？謝謝。

Maybe Tolga, a question for you. I mean I think we spoke to Q1 phasing and that's actually kind of very typical in the industry. But Tolga, do you want to --

托爾加，或許我有個問題想問你。我的意思是，我們之前討論過第一季的進度安排，這在業界其實很常見。但是托爾加，你願意嗎？--

Right. So I would actually really step back and start thinking about rather than on a monthly fluctuations looking at the quarterly -- the total growth of this category. If you think about the historically, while quarterly growth has fluctuated, the longer-term category trend has been one of robust and really well sustained growth. On the order of about 40 plus over the past several years. So even within Q4, we've seen momentum improved as we exited the quarter.

正確的。因此，我實際上會退後一步，開始思考，與其專注於每月的波動，不如專注於該類別的季度總成長。從歷史角度來看，雖然季度成長率有所波動，但長期來看，該類別的發展趨勢是強勁且持續成長的。過去幾年裡，大約有 40 多例。因此，即使在第四季度，我們也看到隨著季度末的臨近，發展勢頭有所改善。

Now, as Yvonne highlighted, Q1 has been rather specific for across the industry in terms of the seasonality. We're certainly seeing some of that, but we believe that from that seasonality is really not impacting the underlying momentum that we're building in the category.

正如伊馮娜所強調的那樣，就季節性而言，第一季對整個產業來說都相當特殊。我們當然看到了一些這樣的現象，但我們認為這種季節性因素實際上並沒有影響我們在該品類中正在建立的潛在發展動能。

Thank you. Next question, please.

謝謝。下一個問題。

Ritu with TD Cowen.

Ritu 與 TD Cowen 合作。

Good morning guys. Thanks for taking the question. I wanted to ask about the gross to net pattern over 2026. Tolga, you mentioned mid-single digits. Is that going to be sort of a stepwise adjustment in Q1 and then flat through the rest of the year? Or is it going to be gradual? Basically, I'm asking are all the access discussions for the full year done?

各位早安。感謝您回答這個問題。我想詢問一下 2026 年的總收入與淨收入的變化趨勢。托爾加，你提到個位數。第一季會逐步調整，然後全年保持穩定嗎？還是會循序漸進？我其實想問的是，全年的所有權限討論都結束了嗎？

And also, if you can comment about per Salveen's question whether potential longer-term competitive dynamics are factoring into how you're thinking about gross to net over the year. Thanks.

另外，如果您能就 Salveen 提出的問題發表評論，即潛在的長期競爭動態是否會影響您全年對毛利潤與淨利潤的考量，那就太好了。謝謝。

Maybe, Jeff, you start on the general gross net question and Tolga may have some additional perspective.

傑夫，或許你可以先從一般的毛淨值問題著手，托爾加可能會有一些額外的見解。

Yeah, Ritu, again, the guidance for the US market for pricing this year is a mid-single-digit net price decrease similar to what we did in '25, and that would be expected to be gradual over the course of the year rather than sort of all upfront in the first quarter, gradual.

是的，Ritu，今年美國市場的定價指導是淨價格下降個位數中段，類似於我們在 2025 年的做法，而且預計這一降幅將在一年內逐步實現，而不是在第一季一次性全部實現。

Yeah. And in terms of the '27 outlook, as we highlighted, it's really too soon for us to make any comments at this point. We don't know what that data is going to look like. We don't know what their label is going to look like. But what I can say is, given how well we're positioned in terms of Part B versus Part D, we believe actually we're really well positioned in terms of being able to manage our our growth.

是的。至於 2027 年的展望，正如我們所強調的，現在發表任何評論都為時過早。我們不知道這些數據會是什麼樣子。我們不知道他們的標籤會是什麼樣子。但我可以肯定的是，鑑於我們在 B 部分與 D 部分之間的優勢，我們相信我們在管理自身成長方面實際上處於非常有利的地位。

And in fact, if you think about the guidance that we provided or I should say, our objectives from 2030, we're ensuring that our 2030 CAGR growth of 25% certainly incorporates some of that thinking. We believe we're going to be able to preserve and increase the value of this category.

事實上，如果你想想我們提供的指導，或者我應該說，我們2030年的目標，我們正在確保2030年複合年增長率達到25%，這其中肯定包含了這些想法。我們相信我們能夠維持並提升這一類別的價值。

Maury with Jefferies.

莫里與傑富瑞。

Hi, good morning. Thanks for taking my question. You commented a little bit on this at JPMorgan, but just wondering for the 5-year strategy, you've mentioned the select external innovation as part of the approximately 30% revenue R&D spend. Can you just elaborate on that? Should we anticipate additional partnerships like the Roche one with zilebesiran or other forms of licensing? And is there anything more on timing, size and scope of an external BD deal?

您好，早安。謝謝您回答我的問題。您在摩根大通對此略作評論，但我想了解一下五年策略，您提到將選擇性外部創新作為約佔收入 30% 的研發支出的一部分。能詳細解釋一下嗎？我們是否應該期待出現像羅氏與齊萊貝西蘭（zilebesiran）的合作或其他形式的授權合作？關於外部業務拓展交易的時間、規模和範圍，還有其他需要說明的地方嗎？

Yeah. Thanks for that question. Look, I think it's important to highlight that we really are focused on our rich internal pipeline, which is truly spring loaded for growth. But given our strengthening financial position, it does make sense to start to become open to select innovation that could provide access to technologies and earlier stage medicines that are complementing our existing commercial portfolio and R&D pipeline. And I think it's important also to state that we have a very high scientific and financial bar both for our internal innovation but also as we look to assess opportunities externally as well.

是的。謝謝你的提問。我認為有必要強調的是，我們真正專注於我們豐富的內部人才儲備，這為成長奠定了堅實的基礎。但鑑於我們不斷增強的財務狀況，開始對一些創新持開放態度，這些創新可以提供技術和早期藥物，以補充我們現有的商業產品組合和研發管線，這確實是有意義的。我認為同樣重要的是要說明，我們對內部創新以及評估外部機會都設定了非常高的科學和財務標準。

Thank you. Next question.

謝謝。下一個問題。

Tazeen with Bank of America.

Tazeen就職於美國銀行。

Hi, good morning. Thanks for taking my question. You talked about the time that you could potentially launch at the beginning of the 2030s. I say, 2030-ish. How should we be thinking about the impact to your operating margin once that product becomes available -- and just practically speaking, even if it might have the better profile that you described of less frequent dosing, how long do you think it would take for patients to appreciate something like that vis-a-vis switching from AMVUTTRA to nucresiran when it becomes available? Thanks.

您好，早安。謝謝您回答我的問題。您曾提到可能會在 2030 年代初推出產品。我覺得大概在2030年左右。我們該如何看待該產品上市後對您的營業利益率的影響？實際上，即使它可能像您描述的那樣具有給藥頻率更低的良好特性，您認為患者需要多長時間才能體會到從 AMVUTTRA 換用 nucresiran 的好處？謝謝。

So there are a couple of questions here. I mean I'll just reiterate maybe the remarks that I kind of made earlier, which is, I mean, we're really excited about nucresiran. We believe that if it's successful, which we have high conviction in is going to have a best-in-class profile, which is going to lead to swift patient uptake. And this is going to be without the royalty obligations for the nucresiran. So clearly, this will have a significant positive impact on our margins post 2030. And as I said, we're looking at potentially driving margins to the mid-40s by 2030.

這裡有幾個問題。我的意思是，我只想重申我之前說過的話，那就是，我們對 nucresiran 真的感到非常興奮。我們相信，如果它成功（我們對此充滿信心），它將擁有同類最佳的品質，這將導致患者迅速接受它。而且這還不包括核苷類似物（nucresiran）的特許權使用費。因此很明顯，這將對我們2030年後的利潤率產生顯著的正面影響。正如我所說，我們希望在 2030 年將利潤率提高到 40% 左右。

And just to tag on to that. I mean, if you look at what consensus gross margins are for our business out to 2030, Tazeen, it's mid-70s. And I would say the vast majority of that is related to the royalty that we pay Sanofi. So that tells you about the opportunity to improve margins post 2030 if we have the kind of profile that we expect with nucresiran.

順便補充一點。我的意思是，塔津，如果你看看市場對我們業務到 2030 年的普遍預期毛利率，那就是 70% 左右。我認為其中絕大部分與我們向賽諾菲支付的專利費有關。所以，這表明，如果我們擁有我們預期中的 nucresiran 的那種特性，那麼在 2030 年後就有機會提高利潤率。

Great. Thank you.

偉大的。謝謝。

Next question, please.

下一個問題。

Luca with RBC Capital Markets.

Luca就職於加拿大皇家銀行資本市場公司。

Oh great. Thanks so much for taking my question. Congrats on the progress. Maybe if I can pivot to the pipeline, Pushkal, can you just talk a little bit about Huntington. Again, I'm assuming that maybe later this year, you'll show some initial pharmacodynamic data and the reduction in mutant (inaudible) CSF, but we all know that Huntington is a relatively slowly progressive disease.

哦，太好了。非常感謝您回答我的問題。恭喜你取得進展。普什卡爾，如果我能把話題轉到管道建設方面，你能稍微談談亨廷頓嗎？我再次假設，或許在今年晚些時候，你們會公佈一些初步的藥效學數據以及突變（聽不清楚）腦脊髓液的減少情況，但我們都知道亨廷頓病是一種進展相對緩慢的疾病。

So I'm assuming that the clinical data like cUHDRS is going to be pretty preliminary, would that be fair? And itself, are you willing to start the pivotal Phase III trial, we just target engagement data in hand? Or are you going to wait before doing so until you see a clear function sign there. So I guess the question is, maybe walk us through what kind of go/no-go decision to start a Phase III trial for Huntington.

所以我認為像 cUHDRS 這樣的臨床數據還相當初步，這樣理解對嗎？那麼，你們是否願意啟動關鍵的 III 期試驗？我們目前的目標就是收集參與數據。或者您打算等到看到明確的功能指示後再採取行動？所以我想問的是，您能否為我們解釋一下，對於亨廷頓舞蹈症，啟動 III 期臨床試驗應該如何做出決定？

Well, that's a great question, and thank you for asking a question about the Huntington's program. It's a program that we have high conviction for addressing what I think we all know is that is an incredibly devastating disease. But of course, a lot of that question, Pushkal.

這是一個很好的問題，感謝您提出有關亨廷頓氏舞蹈症防治計畫的問題。我們非常有信心透過這個計畫來解決我們都清楚的、極具破壞性的疾病。當然，普什卡爾，這個問題還有很多需要解答的地方。

Yes. Luca, happy to address it. As I mentioned, as you highlight, the unmet need in Huntington's, I think is undisputable. We're very excited about the approach we have. We have an siRNA that targets the overall Huntingon's protein, but specifically also target this exon segment that is thought to be necessary actually for disease propagation.

是的。Luca 樂意回答這個問題。正如我所提到的，正如你所強調的，亨廷頓氏舞蹈症方面存在著未被滿足的需求，我認為這是無可爭議的。我們對目前採取的方法感到非常興奮。我們有一種 siRNA，它針對整個亨廷頓蛋白，但同時也專門針對這個被認為對疾病傳播至關重要的外顯子片段。

And so we think we have a very unique approach. I think unfortunately, prior approaches haven't really addressed this. And interestingly enough, the one approach that does is the uniQure approach, and we've all seen some recent data coming from there that suggest potentially through natural history data, there may be a favorable trend there emerging in terms of efficacy.

因此，我們認為我們擁有非常獨特的方法。我認為遺憾的是，以往的方法並沒有真正解決這個問題。有趣的是，唯一有效的方法是 uniQure 方法，而且我們都看到了一些來自該方法的最新數據，這些數據表明，透過自然史數據，在療效方面可能出現了一種有利的趨勢。

So we're very excited about the approach. We're in a Phase I program right now in Huntington's patients where we're really trying to see convincing evidence of lowering of Huntington's as well as to safety. You'll recall that prior efforts in this space have been challenged because they can't get to high levels of knockdown beyond about 20%, and then they've been associated with safety concerns. And (inaudible) increases cerebral ventricular enlargement, et cetera. So I think those are the first 2 things, Luca, that we're going to be looking for.

所以我們對這種方法感到非常興奮。我們目前正在對亨廷頓病患者進行 I 期臨床試驗，我們真的想看到降低亨廷頓病發病率以及安全性的令人信服的證據。您可能還記得，先前這方面的努力受到了挑戰，因為它們無法達到超過 20% 的擊倒率，而且它們也與安全問題聯繫在一起。並且（聽不清楚）增加腦室擴大等。所以我覺得，盧卡，這應該是我們首先要尋找的兩件事。

Can we get to good levels of knockdown, we'd like to get to over 50% and can we do that durably and safely for a period of time. As we've mentioned, we'll put out some data at the end of this year. You're right that I wouldn't expect a lot in terms of clinical data at that point in terms of cUHDRS. This is really relatively modest number of patients. And so -- but we're hoping that, that -- again, if we see those 2 signs. Then to your second part, look, this is, again, given the unmet need, this is a program we're very much going to try and accelerate as quickly as possible.

我們能否達到較高的擊倒率？我們希望達到 50% 以上，並且能否在一段時間內持久、安全地做到這一點？正如我們之前提到的，我們將在今年年底公佈一些數據。你說得對，就 cUHDRS 而言，在那個階段我不會期望獲得太多臨床數據。患者人數確實相對較少。所以——但我們希望——再次，如果我們看到這兩個跡象。然後是你的第二個問題，你看，鑑於目前的需求尚未得到滿足，我們將盡一切努力盡快推進這個專案。

We want to do that in a responsible way. But you look to us to see what -- anything we can do to bring this forward to patients as quickly as possible and keep you posted on that.

我們希望以負責任的方式做到這一點。但你們期待我們能做些什麼，盡快將這項技術推廣給患者，並隨時向你們報告最新進展。

Next question, please.

下一個問題。

Myles with William Blair.

邁爾斯和威廉·布萊爾。

Oh, hey, thanks for taking the questions. Another one on the pipeline for obesity. Just what's the rationale for prioritizing the ACBR1c asset or the (inaudible) for something like (inaudible) in your Phase I trial? And then is the target product profile for that that's going to come out of that data? Is it something that's equivalent to what we're seeing from your peer in Arrowhead or are you going for something superior on the efficacy side? Thanks very much.

哦，嘿，謝謝你回答這些問題。又一項針對肥胖症的藥物正在研發中。在您的 I 期試驗中，優先考慮 ACBR1c 資產或類似（聽不清楚）的（聽不清楚）的理由是什麼？那麼，根據這些數據，我們將得出目標產品概況嗎？它是否與你們在 Arrowhead 的同行產品相當，還是你們在功效方面追求更勝一籌？非常感謝。

Pushkal, that's one straight for you.

普什卡爾，這球直接給你。

Yes. Thanks, Myles. So look, we -- I think we see a tremendous opportunity in the overweight obesity space and the diabetes space. I think GLP-1s have obviously revolutionize that space. But I think we all recognize there's a lot of unmet need to actually aid in weight loss, A1c reduction without the muscle loss and the tolerability issues that happened with GLP-1s.

是的。謝謝你，邁爾斯。所以你看，我們——我認為我們在超重、肥胖和糖尿病領域看到了巨大的機會。我認為GLP-1療法顯然已經徹底改變了這個領域。但我認為我們都意識到，目前有很多未被滿足的需求，即在不造成肌肉流失和耐受性問題的情況下，幫助人們減輕體重、降低糖化血紅蛋白A1c水平，而這些問題正是GLP-1類藥物所造成的。

So we're bringing -- we have prioritized ACBR1c because both I think in our preclinical work, based on the genetics, preclinical models as well as, I think, some of the emerging data that you're seeing coming from Arrowhead. You see that ACBR1c appears to be the more potent target. And so we've certainly prioritized that. We are interested in (inaudible), but we think ACVR1c is more interesting. I think I think the other point here I think is worth noting is that I think when you look at the Arrowhead and Wave data, I think there's questions about the monotherapy magnitude of weight loss that they can deliver.

因此，我們優先考慮 ACBR1c，因為我認為，無論是基於遺傳學、臨床前模型，還是基於 Arrowhead 的一些新興數據，我們的臨床前工作都表明了這一點。你可以看到，ACBR1c 似乎是更有效的標靶。因此，我們當然將此事列為優先事項。我們對（聽不清楚）感興趣，但我們認為 ACVR1c 更有趣。我認為這裡還有一點值得注意，那就是，當你查看 Arrowhead 和 Wave 的數據時，我認為人們對它們能夠帶來的單一療法減肥效果的程度存在疑問。

And I think this is a space where we're going to have to be particularly thoughtful. I think we're uniquely positioned to be thinking about unique patient segments that we might be able to target, looking at unique combinations that can bring disproportionate benefit to patients within this space. So -- but that's the reason for prioritizing ACBR1c. And as I said, we expect to have some results to share at the end of the year.

我認為在這個領域，我們需要格外謹慎思考。我認為我們擁有獨特的優勢，可以思考我們可以瞄準的獨特患者群體，尋找能夠為該領域患者帶來不成比例益處的獨特組合。所以——這就是優先考慮 ACBR1c 的原因。正如我所說，我們預計年底會有一些結果可以分享。

Next question.

下一個問題。

Mike with Morgan Stanley.

麥克在摩根士丹利工作。

Good morning. Thanks for taking the question. Maybe I could ask a question just on cardiomyopathy and trends there particularly for market share. Obviously, you've had some great share gains in the second-line setting and also positive trends in the front line. Just curious, particularly in front line as we move through the year. Do you expect that -- those share trends to continue to increase? Thanks.

早安.感謝您回答這個問題。或許我可以問一個關於心肌病變及其發展趨勢，特別是市場佔有率的問題。顯然，你們在二線市場取得了巨大的份額成長，一線市場也呈現正面的發展趨勢。只是好奇，尤其是在一年中的這個時候，第一線人員的情況更是如此。你認為這些份額成長趨勢會持續下去嗎？謝謝。

Yes. No, we've been very pleased by the sort of broad and balanced kind of access that we're seeing, Tolga?

是的。不，托爾加，我們對目前這種廣泛而平衡的准入方式感到非常滿意？

Yes. I mean, as you saw, Mike, in the data we shared, particularly around new-to-brand dynamics, we're approaching near parity with tafamidis and the goal was there to intent was to demonstrate that in a growing and increasingly competitive category, we've been able to make meaningful and rapid headway. Now in terms of '26, obviously, we have reiterated our full year '26 guidance. And what gives us the confidence is the continuous progress we're making in terms of first-line access, rising physician and patient preference and also importantly, healthy category growth. Those were the drivers heading into JPM, and we'll continue to see them strengthened. And that -- obviously, that momentum supports our outlook for '26.

是的。我的意思是，正如你所看到的，麥克，在我們分享的數據中，尤其是在新品牌動態方面，我們已經接近與 tafamidis 持平，而我們的目標是表明，在一個不斷增長且競爭日益激烈的類別中，我們已經能夠取得有意義的快速進展。至於 2026 年，顯然，我們已經重申了 2026 年全年業績預期。而讓我們充滿信心的，是我們在一線准入方面取得的持續進步、醫生和患者偏好的提高，以及非常重要的，健康的品類增長。這些是推動摩根大通發展的因素，我們將繼續看到這些因素加強。顯然，這種勢頭支撐了我們對 2026 年的展望。

And of course, we're going to be having our TTR webinar in at the end of March, which will be an opportunity. So when you think about how we're going to build this very exciting franchise for the future. Thanks for that plug.

當然，我們將在三月底舉辦 TTR 網路研討會，這將是一個機會。所以，想想我們將如何打造這個令人興奮的未來品牌。謝謝你的推薦。

Next question.

下一個問題。

Ted with Piper Sandler.

泰德和派珀·桑德勒。

Great, thank you very much. And just maybe digging a little bit deeper in terms of the external partnering, should we be more thinking complementary technology then from your comments earlier, Yvonne? whether that be delivery types or other RNA mechanisms? Thanks.

太好了，非常感謝。或許我們可以更深入地探討外部合作，根據你先前的評論，我們是否應該更多地考慮互補技術，伊馮娜？無論是遞送方式還是其他RNA機制？謝謝。

Yeah. No, I think that's absolutely correct. I mean we are looking at areas where there's good strategic fit, so opportunities are complementary to what we're doing. You touched on delivery. That's 1 potential approach to consider.

是的。不，我認為完全正確。我的意思是，我們正在尋找具有良好策略契合度的領域，因此這些機會與我們正在做的事情是互補的。你提到了配送方面的問題。這是可以考慮的潛在方法。

We have a very exciting internal pipeline. So we're going to be very judicious about what exome innovation actually helps us accelerate our internal innovation and also complements our current portfolio. But Pushkal, do you want to add anything to that?

我們擁有非常令人振奮的內部人才儲備。因此，我們將非常謹慎地選擇哪些外顯子組創新能真正幫助我們加速內部創新，並補充我們目前的產品組合。普什卡爾，你還有什麼要補充的嗎？

No, I think you've covered it, Yvonne. I think we're going to be looking at that landscape of things that are complementary from a technology perspective that help us bring medicines to more patients more rapidly.

不，我想你已經講清楚了，伊馮娜。我認為我們將從技術角度審視那些能夠幫助我們更快為更多患者提供藥物的互補事物。

Next question please.

下一個問題。

Ellie with Barclays. Please go ahead.

艾莉在巴克萊銀行工作。請繼續。

Hey guys, thanks for taking the question. Maybe just a big picture one across the sort of emerging early-stage pipeline, which programs are you most excited about? Or do you think are the most derisked? And then a second question, just you mentioned for the US, you expect a mid-single-digit net price decrease in 2026. What would you expect for 2027? Should we expect something similar or potentially more or less with a new competitor? Thanks.

各位，謝謝你們回答這個問題。或許可以從宏觀角度來看目前新興的早期研發項目，你最期待哪些項目？還是你認為風險降幅最大？第二個問題，正如您剛才提到的，對於美國而言，您預計 2026 年淨價格將出現中等個位數的下降。你對2027年有什麼預期？面對新的競爭對手，我們是否應該預期情況會類似，或者可能更糟或更糟？謝謝。

Well, I think it started off with trying to get to see what our favorite programs are, Pushkal?

嗯，我想最初是為了了解我們最喜歡的節目是什麼，Pushkal？

Yeah. I mean, Eli, I think like choosing between your children. So we've got some very exciting opportunities I think in terms of your question about which are most derisked, I think, look, obviously, nucresiran is about as derisked as possible. We obviously have no doubt, but TTR silencing aids in both polyneuropathy and in cardiomyopathy. And with that drug, we'll get to 95% silencing and twice year dosing.

是的。我的意思是，伊萊，我覺得這就像在你的孩子之間做選擇一樣。所以，我認為我們有一些非常令人興奮的機會。至於你問的哪些風險最低，我認為，很明顯，nucresiran 的風險已經降到最低了。我們當然毫不懷疑，TTR 沉默對多發性神經病變和心肌病變都有幫助。有了這種藥物，我們就能達到 95% 的抑制率，並且每年只需服用兩次。

Zilebesiran has shown blood pressure lowering, compelling blood pressure lowering in 4 studies now of Phase I and III Phase IIs of increasing stringency on top of background medicines with a durable profile and there is a wealth as Professor Williams highlighted last year, ESC of data that suggests that continuous control of blood pressure should lead to outsized benefits in terms of cardiovascular outcomes. So I don't think -- I think that's fairly derisked.

Zilebesiran 已顯示出降低血壓的作用，目前在 4 項 I 期和 III 期研究中，以及越來越嚴格的 II 期研究中，均顯示出顯著的降血壓效果，並且具有持久的療效。正如 Williams 教授去年在 ESC 所強調的那樣，有大量數據表明，持續控制血壓應該會在心血管結果方面帶來巨大的益處。所以我覺得——我覺得風險已經相當低了。

I think as you look forward, we have a number of other programs where I think actually in the period of '26 and '27, we are going to get very compelling data that leads to derisking. If you think about data coming out on Huntington's, or as I just mentioned in my comments to Luca in CAA, and we will get some proof-of-concept data on a number of different programs in overweight obesity, diabetes and a number of programs that we actually haven't named. And then, of course, the plasminogen program, where we've already seen convincing data that we shared last year at R&D Day in terms of proof of mechanism that we're seeing clot stabilization, very strong genetics. So I think that's been significantly derisked.

我認為展望未來，我們還有一些其他項目，我認為在 2026 年和 2027 年期間，我們將獲得非常有說服力的數據，從而降低風險。如果你想想亨廷頓氏舞蹈症的數據，或者就像我剛才在CAA上對盧卡提到的那樣，我們將獲得一些關於超重、肥胖、糖尿病以及我們尚未命名的許多不同項目的概念驗證數據。當然還有纖溶酶原項目，我們已經看到了令人信服的數據，我們在去年的研發日上分享了這些數據，證明了我們正在觀察到凝血穩定和非常強大的遺傳機制。所以我認為這方面的風險已經大大降低了。

And you see our confidence in there. We've kicked off on Phase II. We've talked about kicking off a second Phase II. And so we're moving rapidly with that program. So I'm excited about the opportunities that lie ahead. And as I said, a number of exciting potential to help patients and create value.

您可以從中看出我們的自信。第二階段已經啟動。我們已經討論過啟動第二階段（II）。因此，我們正在快速推進該專案。所以我對未來的機會感到興奮。正如我所說，它具有許多令人興奮的潛力，可以幫助患者並創造價值。

Yes, that's great, Pushkal. I think the really unusual story about Alnylam is actually we have a derisked organic product engine. And this gives us tremendous leverage, helping us to kind of accelerate the pace of innovation and allowing us to scale with this proven platform into what's going to be a multi-franchise growth company. And as Pushkal highlighted, there are a number of near-term opportunities for us to really turn these programs and important medicines for patients. Jeff, do you want to add any perspective?

是的，太好了，普什卡爾。我認為 Alnylam 最不尋常的地方在於，我們擁有一個風險降低的有機產品引擎。這給了我們巨大的優勢，幫助我們加快創新步伐，並使我們能夠利用這個經過驗證的平台，發展成為一家多品牌特許經營的成長型公司。正如普什卡爾所強調的那樣，我們有很多近期機會可以真正將這些計畫和重要藥物轉化為對患者有益的成果。傑夫，你還有什麼補充嗎？

Just on the pricing question, I think that Eli had asked about. Again, what we've said consistently, I think since we've launched in the US with the cardiomyopathy and the labels, we've expected gradual net price reductions over time as the business scales. Again, we're entering year 2, right? And year 1 was mid-single-digit price decrease.

關於定價問題，我想 Eli 之前問過。正如我們一直以來所說的那樣，自從我們在美國推出心肌病變相關產品和標籤以來，我們就一直預期隨著業務規模的擴大，淨價格會逐步降低。我們又進入第二年了，對吧？第一年價格下降了個位數百分比。

That's what we're expecting in year two and I would say over the longer-term guidance that we've given, right, 25% CAGR, that's the expectation across the period at this point.

這就是我們對第二年的預期，而且我認為，在我們給予的長期指導中，25% 的複合年增長率，是目前我們對這段時期的預期。

That's great, Jeff. And apologies when we get these multipart questions, sometimes the -- one of the question kind of slips off the list. Tolga, do you have...

太好了，傑夫。對於這種多部分問題，我們深表歉意，有時其中一個問題可能會被遺漏。托爾加，你有…

Yes, I have a multipart answer as well. I mean, look, just to support Jeff's point, in terms of how anticipated new competition may impact the pricing. As we reiterated, first of all, we're really well positioned from an access perspective, we've established credibility and durability of this franchise in '26 and if you think about the potential emerging competition, we're already actually in that competitive field with the polyneuropathy indication. And we've been able to secure great access to the patients with limited co-pay.

是的，我的答案也是分成多個部分給的。我的意思是，你看，為了佐證傑夫的觀點，就預期的新競爭可能會如何影響定價而言。正如我們重申的那樣，首先，從准入角度來看，我們確實處於非常有利的地位，我們在 2026 年建立了這一特許經營權的信譽和持久性，如果你考慮到潛在的新興競爭，我們實際上已經憑藉多發性神經病適應症進入了競爭領域。而且我們已經確保患者能夠以較低的自付費用獲得良好的醫療服務。

So I think I would anticipate -- and obviously, we provided our goals for 2030, and that value growth of 25% (inaudible) remains so we're comfortable with providing that perspective for '27 as well.

所以我認為我可以預期——顯然，我們已經提出了 2030 年的目標，25% 的價值成長（聽不清楚）仍然有效，所以我們也有信心對 2027 年也做出同樣的展望。

Good. Well, I hope we covered everything you asked.

好的。希望我們已經解答了您所有的問題。

Next question, please.

下一個問題。

Cory with Evercore ISI.

Cory，來自 Evercore ISI。

Hey, good morning guys. Thanks for taking the question. I guess it's related somewhat to what you were just talking about. But with the competitive silence or data, obviously expected this year, I'm interested in your latest views on the potential for that asset to attain a differentiated label based on their trial? And how you think about that having a potential commercial impact on AMVUTTRA if it were to actually be the case? Thank you.

嘿，各位早安。感謝您回答這個問題。我想這跟你剛才說的有點關係。但鑑於今年競爭數據方面明顯缺乏進展，我很想聽聽您對該資產能否根據其試驗結果獲得差異化標籤的最新看法？如果情況果真如此，您認為這會對 AMVUTTRA 的商業發展產生怎樣的潛在影響？謝謝。

Okay. Well, I think there's a sort of both a kind of commercial and then also a development kind of perspective on that question. So I think, Tolga, you want to just make a few remarks and then we'll hand it over for Pushkal.

好的。我認為這個問題既可以從商業角度來看，也可以從發展角度來看。所以我想，托爾加，你只需簡單說幾句，然後我們就把發言權交給普什卡爾。

Yes. Before I turn it over to Pushkal, I mean, look, it's obviously difficult to assess the impact without seeing their data, and it would be premature to speculate on the specific role that you're going to play. That said, I think what's really important to highlight is this category remains very large and significantly underserved markets. Additional entrants will certainly help drive diagnostics and treatment rates, which we believe ultimately will benefit patients and expand the category. So from our perspective, we feel very well positioned.

是的。在我把麥克風交給普什卡爾之前，我的意思是，你看，顯然在沒有看到他們的數據的情況下很難評估其影響，現在就猜測你將扮演的具體角色還為時過早。也就是說，我認為真正需要強調的是，這個類別仍然是一個非常龐大且服務嚴重不足的市場。更多的參與者肯定有助於提高診斷和治療率，我們相信這最終將使患者受益並擴大該類別。所以從我們的角度來看，我們感覺自己處於非常有利的地位。

We have a head start given our rapid and deep and sustained knockdown profile, strong clinical data package and obviously convenient quarterly dosing. So maybe, Pushkal, you can --

我們憑藉快速、深入和持續的抑制效果、強大的臨床數據包以及顯然方便的季度給藥方案，已經取得了先機。所以，普什卡爾，或許你可以--

Yes. I think, Cory, I think we are looking forward to seeing the results. Obviously, we don't have a magic crystal ball, we'll see what the results are. But I think our expectation is that the study will be positive. They've shown good knockdown that occurs over a period of some months.

是的。科里，我想我們都很期待看到結果。顯然，我們沒有水晶球，我們只能拭目以待了。但我認為我們預期這項研究的結果會是正面的。他們展現出了良好的擊倒能力，這種能力會在幾個月的時間內逐漸顯現。

And so I would expect, and they have a large outcome study, both in monotherapy and in combination. So I would expect the results to be positive. I think we'll be on the lookout for a couple of aspects of this. First of all, obviously, we want to look at the safety profile that emerges. This is an ASO in a large population that's somewhat older and frailer.

因此，我預計他們會進行一項大型結果研究，包括單藥治療和聯合治療。所以我預計結果會是正面的。我認為我們會關注其中的幾個方面。首先，很顯然，我們要來看看所呈現的安全狀況。這是針對人口眾多、年齡偏大且體弱多病人群的ASO（老年人服務組織）。

So it will be interesting to see how that emerges.

所以，看看最終結果如何，將會很有趣。

And then on the efficacy side, look, I think -- again, I think that I expect to see favorable impacts on the outcome parameters as we've shown with HELIOS-B with vutrisiran. I think there's some speculation that will they have a stronger signal, for example, in the combination because they'll have a larger number of patients on top of a background stabilizer. My hypothesis would be I don't see any reason why the treatment effect size we would be any different than what we've already established in HELIOS-B.

至於療效方面，我認為——同樣，我認為我期望看到對結果參數產生有利的影響，就像我們在 HELIOS-B 中使用 vutrisiran 所顯示的那樣。我認為有人猜測，例如，聯合治療可能會產生更強的信號，因為在背景穩定劑的基礎上，他們將有更多的患者參與治療。我的假設是，我看不出有什麼理由說明我們得到的治療效果大小會與我們在 HELIOS-B 中已經確定的效果大小有任何不同。

Now they may have a tighter confidence interval or stronger p-value in that subgroup, but in terms of the effect size, I don't expect it to be materially different, and I think so it would be consistent with what we saw. Your question is, I think, the most critical one, which is how is that going to impact the label and I would just point out that our label already shows gives -- provides data for both on and office stabilizer.

現在，他們可能會在該子組中獲得更窄的置信區間或更強的 p 值，但就效應量而言，我不認為會有實質性的不同，我認為這與我們看到的結果一致。我認為，你的問題是最關鍵的，那就是這將如何影響標籤，而我只想指出，我們的標籤已經顯示了——提供了在辦公室和辦公室穩定器的數據。

And it specifically points out that the treatment effects were consistent in both populations. And so we have a very broad label. So I don't know how -- I don't foresee how the label would be materially different based on the statistical significance in that one subgroup. But that remains to be seen. But that's how I would map it out.

報告特別指出，治療效果在兩人中均一致。因此，我們的標籤含義非常廣泛。所以我不知道——我預見不到，僅基於該子組的統計顯著性，標籤會有什麼實質性的不同。但這還有待觀察。但我會這樣規劃。

Next question.

下一個問題。

Danielle with Truist.

Danielle，來自 Truist。

Hey guys, this is Alex on for Danielle. Thanks for taking the question. Just a question on AMVUTTRA access in community centers. I guess do you have a sense of how much of the market is not currently accessible due to the high cost of AMVUTTRA and potential hesitancy to stock the drug. Just curious if you have a sense of what proportion of new diagnosis are coming out of the community centers versus what proportion of AMVUTTRA patients are actively being managed in the community settings. Thanks so much.

大家好，我是Alex，替Danielle為您報道。感謝您回答這個問題。請問關於社區中心使用AMVUTTRA卡的問題。我想您應該了解，由於 AMVUTTRA 價格高昂以及商家可能不願進貨，目前有多少市場無法進入。我只是好奇您是否了解，新確診病例中有多少比例來自社區中心，而 AMVUTTRA 患者中又有多少比例在社區環境中接受積極治療。非常感謝。

Yes. I mean, let me just take that very quickly. As we highlighted, from a payer perspective, first and foremost, because I think you highlighted whether there's an access issue, we feel really well positioned from access standpoint again, the large majority of patients have first on access to AMVUTTRA and that's regardless of where those patients are. In terms of accessing the medication, as we highlighted, first of all, our experience is that it's very broad and balanced.

是的。我的意思是，讓我快速地把它拿走。正如我們所強調的，從支付方的角度來看，首先，因為我認為您強調了是否存在准入問題，我們再次感到在准入方面處於非常有利的地位，絕大多數患者都能優先獲得 AMVUTTRA，無論這些患者身在何處。就獲取藥物而言，正如我們所強調的，首先，我們的經驗是，藥物的獲取途徑非常廣泛且均衡。

And in terms of the community saving patients, we've been able to actually secure alternative site of care agreements where 90% of the patients already have AMVUTTRA injection within 10 miles their residences. And we are continuing to expand that network. But I think we reached actually that critical mass already within '25, and we obviously continue to work on that.

在社區拯救患者方面，我們已經能夠確保替代護理地點的協議，其中 90% 的患者已經在距離住所 10 英里範圍內接受了 AMVUTTRA 注射。我們正在不斷擴展這個網路。但我認為我們實際上在 2025 年就已經達到了臨界規模，而且我們顯然會繼續為此努力。

Well, I believe that was our last question. So I'd just like to thank everyone for joining us today. Clearly, 2025 was a remarkable year in which we delivered a blockbuster launch of AMVUTTRA in TTR cardiomyopathy. We made significant advancements across our pipeline and we achieve sustainable profitability. And as we begin this next chapter of our story, we look forward to executing on our 2026 goals and the broader 2030 strategy.

嗯，我想這是我們最後一個問題了。所以，我只想感謝今天到場的各位。顯然，2025 年是意義非凡的一年，我們成功推出了治療 TTR 心肌病變的重磅藥物 AMVUTTRA。我們在產品線各個環節都取得了重大進展，並實現了可持續盈利。隨著我們開啟故事的下一個篇章，我們期待著實現 2026 年的目標和更廣泛的 2030 年策略。

to both accelerate innovation and scale impact. Thanks, everybody, who joined the call, and have a great day.

既能加速創新，又能擴大影響力。感謝所有參加電話會議的人，祝大家今天過得愉快。

Ladies and gentlemen, this concludes today's conference call. Thank you for participating, and you may now disconnect.

女士們、先生們，今天的電話會議到此結束。感謝您的參與，您現在可以斷開連接了。