Alnylam Pharmaceuticals, Inc. (ALNY) 2026 Q3 法說會逐字稿

Hello, everyone. Thank you for joining us, and welcome to the Alnylam Pharmaceuticals Q3 earnings conference call. (Operator Instructions)

各位好。感謝各位加入，歡迎參加 Alnylam Pharmaceuticals 第三季（Q3）財報電話會議。（接線員指示）

Now I hand the conference over to the company. Please go ahead.

現在我把會議交給公司方。請開始。

Good morning. I'm Josh Brodsky, Vice President of Investor Relations at Alnylam. With me today are Yvonne Greenstreet, Chief Executive Officer; Tolga Tanguler, Chief Commercialization Officer; Pushkal Garg, Chief Research and Development Officer; and Jeff Poulton, Chief Financial Officer.

各位早安。我是 Alnylam 投資人關係副總裁 Josh Brodsky。今天與我一同出席的有：執行長 Yvonne Greenstreet；商業化長（Chief Commercialization Officer）Tolga Tanguler；研發長（Chief Research and Development Officer）Pushkal Garg；以及財務長 Jeff Poulton。

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. I'd 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.

對於透過電話會議參與的各位，隨附簡報可至我們網站 investors.alnylam.com/events 的投資人頁面「活動（Events）」區塊取得。我要提醒各位，本次電話會議將包含關於 Alnylam 未來預期、計畫與前景的評論，依據「安全港條款（safe harbor provision）」之目的，這些內容構成前瞻性陳述。

Actual results may differ materially from those indicated by these forward-looking statements as a result of various important risks and uncertainties and including those discussed under the heading Risk Factors in our most recent periodic report available on our website and on file with the SEC. We disclaim any obligation to update such statements.

由於各種重要風險與不確定性（包括我們最近一期定期報告中「風險因素（Risk Factors）」標題下所討論者；該報告可於我們網站及向美國證券交易委員會（SEC）提交之檔案中取得），實際結果可能與這些前瞻性陳述所示有重大差異。我們不承擔更新此類陳述的任何義務。

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

接下來，我把電話交給 Yvonne。Yvonne？

Thanks, Josh, and thank you, everyone, for joining the call today. I'm going to begin by putting the quarter into context and discussing why our commercial portfolio and pipeline give us confidence in our item's growth. Tolga will then review our commercial performance and the work underway to expand AMVUTTRA adoption and support patient access. Pushkal will walk through our decision to further expand TRITON-CM enrollment and important progress across our pipeline. And finally, Jeff will review our Q3 financial results and our outlook for the fourth quarter and full year before we go to Q&A.

謝謝你，Josh，也謝謝各位今天加入本次電話會議。我將先從整體脈絡切入，說明本季表現，並談談為何我們的商業產品組合與研發管線讓我們對公司成長充滿信心。接著 Tolga 會回顧我們的商業表現，以及目前正在進行的工作，以擴大 AMVUTTRA 的採用並支持病患取得治療。Pushkal 會說明我們決定進一步擴大 TRITON-CM 的收案，以及研發管線的重大進展。最後，Jeff 會回顧第三季財務結果，並在進入問答前，提供第四季與全年展望。

I want to start by why we remain confident in the opportunity ahead of Alnylam. And AMVUTTRA has demonstrated significant benefits for patients with ATTR cardiomyopathy including reductions in mortality and cardiovascular events with quarterly dosing. We believe that this profile and AMVUTTRA's unique mechanism of action, position it to become a foundational treatment in a market where many patients remain untreated, and many physicians are still gaining experience with the medicine.

我想先談談為何我們仍對 Alnylam 未來的機會充滿信心。AMVUTTRA 已在 ATTR 心肌病變患者中展現顯著效益，包括在每季給藥的情況下，降低死亡率與心血管事件。我們相信，這樣的特性以及 AMVUTTRA 獨特的作用機轉，使其有望成為一個基礎性治療；在這個市場中，仍有許多患者尚未接受治療，且許多醫師仍在累積對該藥物的使用經驗。

Now moving on to the quarter. Our third quarter product revenues grew 52% year-over-year to approximately $1.3 billion, led by continued AMVUTTRA uptake, establishing a strong foundation for our TTR franchise. We generated total TTR revenues of $1.15 billion during the third quarter, representing nearly 60% growth year-over-year. We have deep conviction in the commercial initiatives and investments we authorized earlier this year and have now fully implemented.

接著談本季表現。我們第三季產品營收年增 52%，至約 13 億美元，主要由 AMVUTTRA 持續放量所帶動，為我們的 TTR 產品線奠定了堅實基礎。第三季我們的 TTR 總營收為 11.5 億美元，年增近 60%。我們對今年稍早核准並已全面落地的商業計畫與投資措施，抱持高度信心。

Given the magnitude of the opportunity in front of us, we believe these are the right actions to broaden AMVUTTRA's prescriber base, deepen physician engagement and over time, drive adoption at scale. That said, we are not yet satisfied with the underlying demand growth we have observed, and this is reflected in the full year outlook that Jeff will discuss shortly.

鑑於我們面前機會的規模，我們相信這些行動是正確的，能夠擴大 AMVUTTRA 的開立醫師基礎、加深醫師互動，並隨時間推進，推動規模化採用。不過，我們對目前觀察到的基礎需求成長仍未感到滿意，這也反映在 Jeff 稍後將說明的全年展望之中。

As Tolga will describe in more detail, our sales force expansion is increasing physician engagement, but that engagement takes time to translate into additional patient starts. We have more work to do and accelerating that translation is a clear priority for us, with what we believe is a best-in-class clinical profile demonstrated by continued evidence generation from HELIOS-B and AMVUTTRA continues to offer a significant opportunity to expand physician adoption and reach more patients in a growing ATTR market.

如 Tolga 將更詳細說明，我們擴編的銷售團隊正在提升與醫師的互動，但這些互動需要時間才能轉化為更多新病患開始用藥。我們仍有更多工作要做，而加速這種轉化是我們明確的優先事項；我們相信，憑藉 HELIOS-B 持續產出證據所展現的同級最佳（best-in-class）臨床特性，AMVUTTRA 仍提供顯著機會，可擴大醫師採用並觸及更多患者，因應持續成長的 ATTR 市場。

And at the same time, the performance of our TTR franchise is funding the future drivers of our Alnylam Group. We're investing in and advancing the next wave of medicines as we build a more diversified, multi-franchise business.

同時，我們 TTR 產品線的表現也在為 Alnylam 集團未來的成長動能提供資金支持。我們正投資並推進下一波藥物，打造更為多元、跨多個產品線（multi-franchise）的業務版圖。

Within the TTR category, Nucresiran gives us the opportunity to build on AMVUTTRA success with deeper TTR lowering and twice yearly dosing. We have a high level of conviction and a positive TRITON-CM outcome. And today, we announced further expansion of enrollment in the study to approximately 2,250 patients. This expansion optimizes the Nucresiran chances for success and strengthens our long-term TTR position.

在 TTR 領域內，Nucresiran 讓我們有機會在 AMVUTTRA 成功的基礎上更進一步，實現更深度的 TTR 降低，並採每年兩次給藥。我們對 TRITON-CM 取得正向結果抱持高度信心。今天我們也宣布，將該研究的收案進一步擴大至約 2,250 名患者。此一擴增可最佳化 Nucresiran 的成功機率，並強化我們長期在 TTR 領域的地位。

Pushkar will go into more detail, but importantly, this expansion does not change our expected ATTR Friday-Monday launch timing of 2030, subject to positive study results and regulatory approval. Beyond TTR, the early Brezosiran results we recently reported in Huntington's disease are particularly encouraging. The target engagement and safety findings to date support our preparations to initiate a pivotal study in 2027, pending regulatory alignment.

Pushkar 會進一步說明，但重要的是，這項擴增不會改變我們對 2030 年 ATTR「週五到週一（Friday-Monday）」上市時程的預期；前提是研究結果為正向且獲得監管核准。在 TTR 之外，我們近期在亨丁頓氏症所公布的 Brezosiran 早期結果尤其令人鼓舞。截至目前的標的結合（target engagement）與安全性發現，支持我們在與監管機關達成一致後，準備於 2027 年啟動關鍵性（pivotal）研究。

Longer term, our Alnylam 2030 vision continues to guide our priorities and investments for the next half of the decade. Our Alnylam 2030 represents our aspiration to become the leading science-driven, fully integrated global biopharmaceutical company, and to maximize the full potential of RNAi therapeutics for patients. It also means driving commercial execution with laser-like focus and urgency, while continuing to invest in the science that can sustain our Alnylam's growth over time. We have a substantial opportunity in front of us, and our responsibility is to turn it into results for patients and shareholders.

從更長期來看，我們的 Alnylam 2030 願景持續引導我們在未來五年後半段的優先事項與投資方向。Alnylam 2030 代表我們的願景：成為以科學驅動、全面整合的全球生物製藥領導公司，並為患者最大化 RNAi 治療的全部潛力。這也意味著以高度聚焦與緊迫感推動商業執行，同時持續投資於能夠長期支撐 Alnylam 成長的科學。我們面前有龐大的機會，而我們的責任是把它轉化為對患者與股東的成果。

With that, let me now turn the call over to Tolga, who will take you through our commercial progress, including our efforts to expand the prescriber base and reach more patients. Tolga?

接下來，我把電話交給 Tolga，由他帶各位了解我們的商業進展，包括擴大開立醫師基礎並觸及更多患者的努力。Tolga？

Thanks, Yvonne, and good morning. We delivered significant year-over-year growth in the third quarter, and continued to bring our therapies to more patients around the world. Today, I will discuss what drove our revenue, where underlying demand has room to grow, and the plans we have in place to capture the opportunity ahead.

謝謝你，Yvonne，各位早安。我們在第三季實現顯著的年增成長，並持續將我們的療法帶給全球更多患者。今天我將說明營收成長的驅動因素、基礎需求仍可提升之處，以及我們為掌握未來機會所制定的計畫。

In the third quarter, we generated $1.29 billion in combined net product revenues, an increase of 52% year-over-year, and 10% compared with the second quarter, including the impact of foreign exchange. This performance reflects continued execution across our portfolio, led by the TTR franchise, and complemented by our rare disease therapies.

第三季我們合計淨產品營收為 12.9 億美元，年增 52%，較第二季增加 10%，其中包含外匯影響。此一表現反映我們在整體產品組合上的持續執行力，以 TTR 產品線為主軸，並由罕見疾病療法加以補強。

Turning to our TTR franchise, global net product revenues reached $1.15 billion in the third quarter, increasing 12% compared with Q2, and 59% year-over-year. In the US, TTR revenues increased 12% sequentially and 69% year-over-year. This approximate $100 million in US quarter-over-quarter revenue growth was driven primarily by an $81 million increase in demand, along with an inventory benefit of $17 million. Net price during Q3 modestly increased from Q2 and benefited from approximately $10 million in one-time gross-to-net adjustments. Jeff will cover these items in more detail.

談到我們的 TTR 產品線，第三季全球淨產品營收達 11.5 億美元，較第二季增加 12%，年增 59%。在美國，TTR 營收較前一季增加 12%，年增 69%。美國單季營收約 1 億美元的季增，主要由需求增加 8,100 萬美元所帶動，另有 1,700 萬美元的庫存效益。第三季淨價格較第二季小幅上升，並受惠於約 1,000 萬美元的一次性總額轉淨額（gross-to-net）調整。Jeff 將更詳細說明這些項目。

Outside the US, TTR revenues increased 10% sequentially and 28% year-over-year. Year-over-year growth was primarily driven by ATTR's CM uptake in Japan and Germany, partially offset by the impact of CM launch price reductions. We're excited by the speed with which we are obtaining access in new markets across Europe. With favorable pricing, recognizing the value of AMVUTTRA over stabilizers, ex-US markets have contributed significantly to tafamidis growth over time, and there is significant opportunity here to support our TTR global leadership ambitions.

在美國以外，TTR 營收較前一季成長 10%，較去年同期成長 28%。年增主要由 ATTR 的 CM 在日本與德國的採用提升所帶動，但部分被 CM 上市價格下調的影響所抵銷。我們對於在歐洲新市場取得准入的速度感到振奮。在有利的定價下，市場認可 AMVUTTRA 相較於穩定劑的價值，美國以外市場長期以來對 tafamidis 的成長貢獻顯著，且在此仍有重大機會支持我們成為全球 TTR 領導者的企圖。

Taken together, these results reflect sustained global growth across the TTR franchise. Looking beyond quarterly revenue, we continue to see encouraging indicators of expansion across the US TTR market and the AMVUTTRA prescriber base. Total ATTR CM prescriptions grew nearly 40% year-over-year in the third quarter. While the rate of growth can vary quarter-to-quarter, category growth continues to be robust and sustained. What's more, approximately 80% of prevalent ATTR CM patients remain untreated, underscoring the substantial long-term potential to bring therapy to many more patients.

綜合而言，這些結果反映 TTR 產品線在全球持續成長。不僅著眼於單季營收，我們也持續看到美國 TTR 市場與 AMVUTTRA 開立醫師基礎擴張的令人鼓舞指標。第三季 ATTR CM 的總處方量較去年同期成長近 40%。雖然成長速度可能因季度而異，但品類成長仍然強勁且具延續性。此外，約 80% 的既有 ATTR CM 患者仍未接受治療，凸顯將治療帶給更多患者的長期潛力相當可觀。

Since the AMVUTTRA CM launch in the United States, more than 2,000 new unique prescribers have prescribed AMVUTTRA. This metric is particularly encouraging given what we know about prescribing behavior among physicians with AMVUTTRA experience. As we highlighted on our Q2 earnings call, we've seen that utilization deepens with experience. Put it simply, trial begets preference. And only with approximately a third of all active prescribers having prescribed AMVUTTRA to date, we see a significant opportunity to drive broader adoption and deepen utilization. This was a key factor behind our decision to expand our customer-facing teams to broaden our reach and engage more prescribers.

自 AMVUTTRA 在美國以 CM 適應症上市以來，已有超過 2,000 位新的、獨立的開立醫師曾開立 AMVUTTRA。鑑於我們對具 AMVUTTRA 使用經驗之醫師處方行為的了解，這項指標尤其令人振奮。如同我們在第二季財報電話會議中強調的，我們看到使用會隨著經驗而加深。簡而言之，試用會帶來偏好。而目前僅約三分之一的所有活躍開立醫師至今曾開立 AMVUTTRA，我們看到推動更廣泛採用並加深使用的重大機會。這也是我們決定擴大面向客戶的團隊、以擴展觸及範圍並接觸更多開立醫師的關鍵因素。

Now, with that expansion in place, we have indeed increased the reach and volume of HCP customer engagements. While these increased engagements have not yet translated into increased demand growth, we are encouraged by the breadth and depth of HCP engagement, positive message resonance, and continued growth in the AMVUTTRA prescribing base with utilization balanced across both centers of excellence and community settings. That said, we recognize there is more work to do to drive demand growth.

如今，隨著擴編到位，我們確實提高了對醫療照護專業人員（HCP）的客戶互動觸及與互動量。雖然這些增加的互動尚未轉化為需求成長的提升，但我們對 HCP 互動的廣度與深度、訊息的正向共鳴，以及 AMVUTTRA 開立醫師基礎的持續成長感到鼓舞，且使用量在卓越中心與社區醫療場域之間保持均衡。不過，我們也認知到仍有更多工作要做，以推動需求成長。

Just 18 months into its ATTR-CM launch, AMVUTTRA already represents approximately 24% of all prescriptions in the total TTR category, including CM and PM, through the end of the third quarter. As launch matures, we will report on total prescriptions, or TRX, which captures both new patient starts and ongoing treatment. Importantly, our share of new-to-brand prescriptions, or NBRX, we previously reported has stayed stable at north of 30% and is helping build a growing base of patients who contribute to recurring prescriptions over time.

在 ATTR-CM 上市僅 18 個月後，截至第三季末，AMVUTTRA 已約占整體 TTR 品類（包含 CM 與 PM）所有處方的 24%。隨著上市進入更成熟階段，我們將改以總處方量（TRX）進行揭露，該指標同時涵蓋新病人起始用藥與持續治療。重要的是，我們先前揭露的新品牌處方占比（NBRX）一直穩定維持在 30% 以上，並有助於建立不斷成長的病人基礎，隨時間推進帶來重複處方。

TRX provides a more comprehensive view of our commercial momentum and the sustained utilization of AMVUTTRA as our patient base grows. Notably, we achieved 24% TRX share with only about a third of category prescribers having tried AMVUTTRA to date. Continued TRX share growth will be driven by deeper utilization among existing prescribers and an expanding breadth of writers, including new-to-category writers who collectively drive significant category prescription growth and further supported by the strong patient adherence associated with AMVUTTRA's quarterly administration.

隨著病人基礎擴大，TRX 能更全面反映我們的商業動能，以及 AMVUTTRA 使用的持續性。值得注意的是，在迄今僅約三分之一的品類開立醫師曾嘗試 AMVUTTRA 的情況下，我們已達成 24% 的 TRX 市占。未來 TRX 市占的持續成長，將由既有開立醫師更深度的使用，以及開立者廣度的擴張所驅動，其中包括新進入該品類的開立者；這些開立者合計推動顯著的品類處方成長，並且在 AMVUTTRA 每季給藥所帶來的高病人依從性支持下，進一步強化成長。

On access, I would like to address two items. First, the proposed CMS rule change that if finalized, as proposed, would substantially reduce Medicare reimbursement for Part B medicines acquired through the 340B drug discount program. The terms of the final rule are not yet known. A final rule is expected imminently and, if implemented, would become effective January 1, 2027, though we do anticipate legal challenges from hospital groups.

在准入方面，我想說明兩點。第一，CMS 擬議的規則變更若最終定案且如提案所述，將大幅降低透過 340B 藥品折扣計畫取得之 Part B 藥品的 Medicare 給付。最終規則的條款目前尚未明朗。預期最終規則將在近期公布，且若實施，將於 2027 年 1 月 1 日生效；不過我們也預期醫院團體將提出法律挑戰。

If the rule is finalized as proposed, we believe that affected health systems may reassess their procurement pathways and or their site-of-care strategies. Protecting patient choice and access to our products will remain our priority. We have multiple options available to mitigate potential risks to patients' access from any final rule reducing reimbursement, including contracting to make discounts available to 340B covered entities and supporting patients in finding alternative sites of care if needed.

若該規則如提案所述最終定案，我們認為受影響的醫療體系可能會重新評估其採購途徑及／或其照護場域（site-of-care）策略。保障病人的選擇權與對我們產品的可近性，將仍是我們的首要任務。針對任何最終規則導致給付降低而可能對病人可近性造成的風險，我們有多種選項可用以降低影響，包括透過簽約使折扣可提供給 340B 覆蓋實體（covered entities），以及在需要時協助病人尋找替代的照護場域。

We will remain closely engaged with health systems as the rulemaking process progresses and will be prepared to respond as greater clarity emerges. Importantly, AMVUTTRA has broad and favorable access with approximately 99% of covered lives having access and approximately 90% of patients able to receive treatment within approximately 10 miles of where they live. Beyond the potential 340B reimbursement changes, we continue to see the normal evolution of payer policies as 2027 negotiations have progressed. As part of that evolution, effective October 1, UnitedHealth implemented a more restrictive first-line AMVUTTRA policy in the Medicare Advantage portion of the market.

隨著規則制定流程推進，我們將持續與醫療體系保持密切互動，並在情勢更明朗時做好回應準備。重要的是，AMVUTTRA 具備廣泛且有利的准入，約 99% 的受保人群可取得用藥，且約 90% 的病人能在距離住處約 10 英里內接受治療。除 340B 給付變更的潛在影響外，隨著 2027 年度談判推進，我們也持續看到付款方政策的正常演進。作為該演進的一部分，自 10 月 1 日起，UnitedHealth 在 Medicare Advantage 市場區塊實施了更為嚴格的 AMVUTTRA 一線用藥政策。

Importantly, this is not expected to impact existing patients and there is an exception process that allows appropriate new patients to access AMVUTTRA first-line. We therefore do not expect an impact to existing patients, though these additional requirements could create some delays for new patients going forward. Our patient support services and field reimbursement teams have significant experience supporting patients' access where step therapy is in place. As we have done in the commercial portion of our business, we remain focused on navigating these changes and protecting patient access to AMVUTTRA.

重要的是，預期這不會影響既有病人，且有例外申請流程可讓合適的新病人以一線方式取得 AMVUTTRA。因此，我們不預期對既有病人造成影響，但這些額外要求可能會使未來新病人的取得流程出現一些延遲。我們的病人支持服務與外勤給付團隊在有階梯療法（step therapy）情況下協助病人取得用藥方面，具備豐富經驗。如同我們在商業保險市場所做的，我們仍將專注於因應這些變化並保障病人對 AMVUTTRA 的可近性。

Taken together, we remain confident in the underlying fundamentals of the TTR franchise and encouraged by the continued growth and expanding reach of AMVUTTRA. We also recognize the work ahead and we remain focused on execution, expanding patient reach, and actively navigating the evolving access environment.

綜合而言，我們對 TTR 產品線的基本面仍具信心，並對 AMVUTTRA 的持續成長與觸及範圍擴大感到鼓舞。我們也認知到前方仍有工作要完成，並將持續專注於執行力、擴大病人觸及，以及積極因應不斷演變的准入環境。

With that, I will now turn the call over to Pushkar.

接下來，我將把電話會議交給 Pushkar。

Thanks, Tolga, and good morning, everyone. Today, I will cover why we remain confident in TRITON-CM, the rationale behind the enrollment expansion of our reference this morning, and the progress we are making beyond TTR, particularly with Brezosiran and Huntington’s disease.

謝謝你，Tolga，各位早安。今天我將說明為何我們對 TRITON-CM 仍具信心、我們今早所提到之入組擴增的依據，以及我們在 TTR 以外領域的進展，特別是 Brezosiran 與亨丁頓氏病。

Alnylam is well-positioned to build durable leadership in TTR. As we have discussed, we believe AMVUTTRA has a differentiated clinical profile that supports its being the first-line treatment of choice for patients with ATTR-CM. AMVUTTRA has demonstrated substantial improvement in clinical outcomes, function, and quality of life, and its treatment effect is preserved irrespective of background medications, including TTR stabilizers. It has a quarterly dosing profile that supports high adherence.

Alnylam 已具備良好條件在 TTR 領域建立持久的領導地位。如同我們先前討論的，我們相信 AMVUTTRA 具備差異化的臨床特性，支持其成為 ATTR-CM 病人的首選一線治療。AMVUTTRA 已證實可在臨床結局、功能與生活品質方面帶來顯著改善，且其治療效果不受背景用藥影響，包括 TTR 穩定劑。其每季一次的給藥特性有助於維持高依從性。

We are poised to extend our leadership beyond AMVUTTRA with Nucresiran, our next-generation investigational TTR silencer, which we believe has the potential for even greater efficacy by a deeper knockdown, over 95% with just two doses per year. As you know, Nucresiran continuing to advance for both hereditary ATTR polyneuropathy and ATTR cardiomyopathy in the Phase 3 TRITON studies.

我們也已準備好透過 Nucresiran（我們下一代、研發中的 TTR 沉默劑）將領導地位延伸至 AMVUTTRA 之外；我們相信其可透過更深度的抑制帶來更高的療效潛力——每年僅需兩次給藥即可達到超過 95% 的 knockdown。如各位所知，Nucresiran 正在第 3 期 TRITON 研究中持續推進，用於遺傳性 ATTR 多發性神經病變與 ATTR 心肌病變兩項適應症。

Recent data from the CARDIO-TTRansform study have reinforced our confidence in the TRITON-CM study, but as I'll explain, we intend to increase the sample size by 500 patients to further enhance the probability of success.

CARDIO-TTRansform 研究的最新數據進一步強化了我們對 TRITON-CM 研究的信心，但正如我將說明的，我們打算將樣本數增加 500 名患者，以進一步提高成功的機率。

Now, as we've previously shared, we believe three factors may have contributed to the failure of NUCRESIRAN to meet its primary endpoint in the CARDIO-TTRansform study. One, NUCRESIRAN is an ASO that achieved much less TTR knockdown than vutrisiran. At under 70%, it seems this was not enough to drive enough of a clinical benefit.

現在，如同我們先前分享的，我們認為有三項因素可能導致 NUCRESIRAN 在 CARDIO-TTRansform 研究中未能達成其主要終點。第一，NUCRESIRAN 是一種 ASO，其 TTR 降低幅度遠低於 vutrisiran。在低於 70% 的情況下，這似乎不足以帶來足夠的臨床效益。

Two, patient selection matters. It stands to reason that patients earlier in their disease course will benefit most from a silencing approach, and we saw that in HELIOS-B. The enrollment in CARDIO-TTRansform of more advanced patients may have further impaired the ability of NUCRESIRAN to deliver significant clinical benefit. And third, their endpoint was not optimized for success. CARDIO-TTRansform focused on cardiovascular mortality in their primary composite endpoint, which fails to capture the multisystem nature of ATTR cardiomyopathy.

第二，患者選擇很重要。合理推論是，病程較早期的患者最能從沉默療法中受益，而我們在 HELIOS-B 中也看到了這一點。CARDIO-TTRansform 納入較晚期患者，可能進一步削弱了 NUCRESIRAN 帶來顯著臨床效益的能力。第三，他們的終點設計並未針對成功進行最佳化。CARDIO-TTRansform 在其主要複合終點中聚焦於心血管死亡，未能捕捉 ATTR 心肌病的多系統特性。

The key learnings I just outlined are things we've understood from our own clinical trials over the years, and which we incorporated into the original design of TRITON-CM. From the outset, we've enriched our study for patients with early disease who are anticipated to have the largest treatment effect. In addition, our study is an event-driven study with an endpoint of all cause mortality and recurrent CV events. As noted, we believe ACM is a more sensitive endpoint in this disease than CV mortality, and an event-driven study is much more robust than a time-bound endpoint.

我剛才概述的關鍵學習，是我們多年來從自身臨床試驗中所理解並已納入 TRITON-CM 原始設計的內容。從一開始，我們就讓研究更聚焦於預期治療效果最大的早期病患。此外，我們的研究是事件驅動型研究，其終點為全因死亡與反覆發生的心血管事件。如前所述，我們認為在此疾病中，全因死亡（ACM）比心血管死亡更敏感，而事件驅動型研究也比時間界定型終點更為穩健。

That said, we have taken this opportunity to evaluate TRITON-CM in the context of the data from CARDIO-TTRansform in order to maximize the probability of study success. An important learning that was reinforced in CARDIO-TTRansform is that the care of patients with ATTR-CM is very rapidly evolving, with earlier diagnosis and treatment, and greater use of background therapies such as SGLT2 inhibitors.

儘管如此，我們也把握這個機會，結合 CARDIO-TTRansform 的數據來評估 TRITON-CM，以最大化研究成功的機率。CARDIO-TTRansform 再次強化的一項重要學習是：ATTR-CM 患者的照護正在快速演進，包括更早的診斷與治療，以及更廣泛使用如 SGLT2 抑制劑等背景治療。

While we remain confident in increased risk potential to deliver a strong treatment effect in this setting, these secular trends do tend to reduce event rates, which can compromise study power. As such, we are announcing today that we are amending the protocol to further increase the sample size by 500 patients to a total of 2,250 patients to address the potential risk of lower-than-expected event rates. This larger sample size will ensure adequate study power under quite conservative estimates of event rates.

雖然我們仍對在此情境下提供強勁治療效果的潛力充滿信心，但這些長期趨勢確實傾向於降低事件發生率，可能削弱研究的統計效能。因此，我們今天宣布將修訂試驗方案，將樣本數再增加 500 名患者，總計達 2,250 名患者，以因應事件發生率可能低於預期的風險。在對事件率採取相當保守的估計下，這個更大的樣本數將可確保足夠的研究統計效能。

In this expanded population, we will further enrich for early patients who are anticipated to have the largest treatment effect with the use of NT-proBNP inclusion criteria. Importantly, we do not expect this expansion to change our expected launch timeline of approximately 2030, given the speed of enrollment and the ability with more patients to accrue more events. And finally, as we have previously said, we will continue to monitor the ongoing study and consider refinements to the study analysis plan down the road, if warranted.

在這個擴大的族群中，我們將透過 NT-proBNP 納入標準，進一步提高早期患者的比例，因其預期具有最大的治療效果。重要的是，考量到入組速度，以及患者數增加可累積更多事件，我們預期此擴增不會改變約 2030 年的預計上市時程。最後，如同我們先前所說，我們將持續監測進行中的研究，並在必要時於未來考慮對研究分析計畫進行調整。

Moving on, Alnylam is progressing a broad pipeline of medicines beyond TTR, with over 25 clinical programs spanning multiple therapeutic areas, representing a significant opportunity to improve patient health and create value in the years ahead. Today, I would like to focus on our program in Huntington's disease, which we have announced we are advancing to a pivotal trial pending regulatory alignment.

接下來，Alnylam 正在推進一條超越 TTR 的廣泛藥物研發管線，擁有超過 25 個臨床計畫，涵蓋多個治療領域，代表未來數年改善患者健康並創造價值的重大機會。今天，我想聚焦於我們在亨丁頓氏病的計畫；我們已宣布在與監管機構達成一致後，將推進至關鍵性試驗。

Huntington's disease is a progressive, fatal neurodegenerative disease. Symptoms typically appear in midlife, during prime working and family years, affect motor, cognitive, and emotional health, with patients' average lifespan shortened to approximately 10 to 30 years from diagnosis. We estimate there are more than 100,000 symptomatic patients globally, with many more individuals who may be pre-symptomatic or undiagnosed.

亨丁頓氏病是一種進行性、致命的神經退化性疾病。症狀通常在中年出現，正值工作與家庭的黃金時期，影響運動、認知與情緒健康；患者的平均壽命自確診起縮短至約 10 至 30 年。我們估計全球有超過 100,000 名有症狀患者，另有更多個體可能處於前症狀期或尚未被診斷。

Huntington is a well-known, genetically validated target for Huntington's disease, which is caused by an expanded CAG repeat in the first exon of the Huntington gene. Individuals who inherit an allele with 40 or more repeats are expected to develop Huntington's disease during their lifetime. The mutant gene can give rise to more than one protein species, a longer, full-length mutant Huntington's protein, and a shorter mutant HTT1a isoform. Both full-length HTT and HTT1a are implicated as toxicity drivers. However, many approaches to date have failed to address the shorter HTT1a isoform.

Huntington（HTT）是一個眾所周知且經遺傳學驗證的亨丁頓氏病治療標的；該疾病由亨丁頓基因第一外顯子中的 CAG 重複序列擴增所致。遺傳到含有 40 次或以上重複的等位基因者，預期在其一生中會發展為亨丁頓氏病。突變基因可產生不只一種蛋白型態：較長的全長突變 Huntington 蛋白，以及較短的突變 HTT1a 同功型。全長 HTT 與 HTT1a 皆被認為是毒性驅動因子。然而，迄今許多方法未能處理較短的 HTT1a 同功型。

At the EHDN conference in Poland this past week, we announced interim results from a Phase 1 study of Brezosiran in patients with Huntington's disease. Encouragingly, we saw robust dose-dependent reductions in CSF mutant Huntington after a single dose. Across two assays, we saw mean maximum reductions of CSF mutant Huntington's of 60% to 64%, with individual reductions up to 83%. Across the five cohorts included in this analysis, no dose-dependent safety signals have been observed to date, with few serious adverse events reported thus far.

在上週於波蘭舉行的 EHDN 會議上，我們公布了 Brezosiran 在亨丁頓氏病患者中的第 1 期研究期中結果。令人鼓舞的是，單次給藥後，我們觀察到腦脊髓液（CSF）中突變 Huntington 蛋白呈現強勁且具劑量依賴性的下降。在兩種檢測方法中，我們觀察到 CSF 突變 Huntington 蛋白的平均最大降幅為 60% 至 64%，個別降幅最高達 83%。在本次分析納入的五個隊列中，迄今未觀察到任何具劑量依賴性的安全性訊號，目前嚴重不良事件的通報也不多。

Importantly, we haven't observed any dose-dependent increases in CNS inflammatory signals, white blood cells, or total protein to date. Likewise, we have not seen increases in neurofilament light chain in the CSF or evidence of ventricular enlargement, despite the high degree of HTT lowering we've been able to achieve. This is in contrast to other programs and an encouraging signal of safety and tolerability.

重要的是，迄今我們未觀察到中樞神經系統（CNS）發炎訊號、白血球或總蛋白出現任何具劑量依賴性的上升。同樣地，儘管我們達成了高度的 HTT 降低，仍未見腦脊髓液中的神經絲輕鏈（neurofilament light chain）上升，或腦室擴大的證據。這與其他計畫形成對比，並是令人鼓舞的安全性與耐受性訊號。

These results give us confidence to advance verzosoran through two complementary studies in parallel. The ongoing Phase 1b open-label extension allows all participants to receive verzosoran every six months. This will enable us to continue characterizing the long-term safety of sustained HTT lowering and to explore potential efficacy trends over time.

這些結果讓我們有信心，並行推進 verzosoran 的兩項互補研究。正在進行的第 1b 期開放標籤延伸研究，讓所有參與者可每六個月接受一次 verzosoran。這將使我們能持續刻畫長期、持續性 HTT 降低的安全性，並探索隨時間推移可能出現的療效趨勢。

At the same time, pending regulatory alignment, we're investing in a large placebo-controlled pivotal study which we plan to initiate in 2027. This study is intended to provide a definitive test of whether brezosiran can slow Huntington's disease progression and will be the first placebo-controlled test of the HTT1a lowering hypothesis. For more about Brezosiran, the recent data, and the overall opportunity, I encourage you to watch the replay of the RNA roundtable we hosted earlier this week available on our website.

同時，在與監管機構達成一致後，我們正投資一項大型安慰劑對照的關鍵性研究，計畫於 2027 年啟動。此研究旨在對 brezosiran 是否能減緩亨丁頓氏病進展提供決定性的檢驗，並將是首個針對降低 HTT1a 假說的安慰劑對照測試。若想了解更多關於 Brezosiran、最新數據與整體機會，我建議您觀看我們本週稍早在官網提供的 RNA 圓桌會議重播。

Wrapping up, we have a few remaining pipeline goals to deliver for 2026. We plan to share Phase 1 healthy volunteer data for ALN-6400 and bleeding disorders at the ASH annual meeting in December. We expect to share the Phase 2 HHT results for ALN-6400 as well as the Phase 1 data for ALN-2232 in obesity on our Q4 and full-year results call in February. We look forward to providing these updates and continuing to advance our pipeline as we execute toward our Alnylam 2030 goals.

最後，我們在 2026 年仍有幾項研發管線目標需要達成。我們計畫在 12 月的 ASH 年會分享 ALN-6400 與出血性疾病的第 1 期健康受試者數據。我們也預期在 2 月的第四季與全年業績電話會議上，分享 ALN-6400 的第 2 期 HHT 結果，以及 ALN-2232 在肥胖症的第 1 期數據。我們期待提供這些更新，並在推進 Alnylam 2030 目標的執行過程中持續推動我們的研發管線。

Let me now turn the call over to Jeff for a review of our third quarter financial results and 2026 outlook. Jeff?

現在我把電話交給 Jeff，請他回顧我們 2026 年第三季的財務結果以及 2026 年展望。Jeff？

Thanks, Pushkal, and good morning, everyone. I'll be presenting the summary of Alnylam third quarter 2026 financial results and discussing our outlook for the balance of the year. Let's begin with a summary of our P&L results for the third quarter. The global net product revenues were approximately $1.3 billion, 52% growth versus Q3 last year, driven by the continued uptake of AMVUTTRA and ATTR cardiomyopathy.

謝謝你，Pushkal，各位早安。我將簡要說明 Alnylam 2026 年第三季的財務結果，並討論我們對今年剩餘期間的展望。我們先從第三季損益表（P&L）結果摘要開始。全球產品淨營收約為 13 億美元，較去年第三季成長 52%，主要受 AMVUTTRA 與 ATTR 心肌病變持續放量所帶動。

As Tolga previously mentioned, third quarter US TTR revenue grew approximately $100 million compared with Q2, with key drivers of growth being an $81 million increase in demand and a $17 million inventory benefit driven by an increase of inventory in the distribution channel from 19 to 21 days. Additionally, net price for Q3 was modestly higher than Q2 and was favorably impacted by a one-time Medicaid-related gross-to-net adjustment of approximately $10 million.

如 Tolga 先前提到，第三季美國 TTR 營收較第二季增加約 1 億美元，成長的主要驅動因素包括需求增加 8,100 萬美元，以及因通路庫存天數由 19 天增加至 21 天所帶來的 1,700 萬美元庫存效益。此外，第三季淨價格較第二季小幅提高，並因一次性與 Medicaid 相關的毛額轉淨額（gross-to-net）調整約 1,000 萬美元而受到正面影響。

The inventory and gross-to-net items supported reported revenue in Q3 but are not measures of underlying demand, and for Q4, we anticipate that both inventory and price in the US will be headwinds to reported growth. For the third quarter, collaboration revenue was $71 million, or an 80% decrease compared with the same period last year. The decrease was primarily driven by the $300 million one-time milestone recognized from Roche in Q3 2025 for dosing the first patient in the ZENITH Phase 3 trial.

庫存與毛額轉淨額項目支撐了第三季的已揭露營收，但並非衡量基礎需求的指標；而在第四季，我們預期美國的庫存與價格兩者都將對已揭露成長形成逆風。第三季合作收入為 7,100 萬美元，較去年同期下降 80%。下降主要是因 2025 年第三季 Roche 就 ZENITH 第三期試驗完成首位病患給藥而一次性認列的 3 億美元里程碑收入所致。

Royalty revenue for the third quarter was $95 million, more than double that of the third quarter last year, driven by higher Leqvio sales. Gross margin on product sales was 72% for the third quarter, representing a 5% decrease compared with Q3 last year. The decrease in margin was primarily driven by increased royalties on AMVUTTRA, as higher revenues in 2026 resulted in an increase in the average royalty rate payable to Sanofi.

第三季權利金收入為 9,500 萬美元，較去年第三季增加逾一倍，主要由 Leqvio 銷售提升所帶動。第三季產品銷售毛利率為 72%，較去年第三季下降 5 個百分點。毛利率下降主要是因 AMVUTTRA 的權利金增加；由於 2026 年營收較高，使得支付給 Sanofi 的平均權利金費率上升。

Our non-GAAP R&D expenses of $376 million increased 21% compared to last year, primarily driven by costs associated with our three ongoing Phase 3 clinical studies, including the ZENITH Phase 3 cardiovascular outcomes trial for Zilebesiran and the TRITON-CM and PN studies for NUCRESIRAN.

我們的非 GAAP 研發費用為 3.76 億美元，較去年增加 21%，主要是由三項正在進行的第三期臨床研究相關成本所驅動，包括 Zilebesiran 的 ZENITH 第三期心血管結局試驗，以及 NUCRESIRAN 的 TRITON-CM 與 PN 研究。

Non-GAAP SG&A expenses of $296 million increased 13% compared to last year, driven primarily by investments in support of the AMVUTTRA ATTR cardiomyopathy launch in the US and in key international markets. We achieved non-GAAP operating income of $425 million, which represents an 11% decrease compared to last year, driven primarily by lower Roche Collaboration revenue that I explained earlier.

非 GAAP 銷售、一般及行政（SG&A）費用為 2.96 億美元，較去年增加 13%，主要由於我們在美國及主要國際市場投入資源，以支援 AMVUTTRA 在 ATTR 心肌病變適應症的上市推廣。我們達成非 GAAP 營業利益 4.25 億美元，較去年下降 11%，主要是受到我先前說明的 Roche 合作收入降低所影響。

We had GAAP net income of $2.2 billion during the quarter, which includes a non-cash benefit from income taxes of approximately $1.9 billion due to the release of Alnylam's US valuation allowance on the majority of its net operating losses and other deferred tax assets, underpinned by the company achieving sustainable profitability. Finally, we ended the third quarter with cash, cash equivalents, and marketable securities of $3.6 billion compared to $2.9 billion as of year-end 2025. The primary driver of the increase in cash year-to-date is our strong operating performance and continued profitability.

本季 GAAP 淨利為 22 億美元，其中包含約 19 億美元的所得稅非現金利益，係因公司達成可持續獲利，進而釋放 Alnylam 在美國針對其大部分淨營運虧損及其他遞延所得稅資產所提列的估值備抵（valuation allowance）。最後，第三季末我們的現金、約當現金及有價證券為 36 億美元，相較於 2025 年底的 29 億美元。今年迄今現金增加的主要原因是我們強勁的營運表現與持續獲利。

Now turning to our full-year outlook. Today, we are reiterating our 2026 guidance as presented during our last earnings call and as summarized on our guidance slide. For TTR product sales, based on performance to date and our expectations for Q4, we expect to land at the low end of our $4.2 billion to $4.5 billion range. As we think about the evolution of our assumptions underlying the guide, there are two main drivers to highlight.

接著談全年展望。今天我們重申 2026 年指引，與上次財報電話會議所提供並在指引投影片中摘要的內容一致。就 TTR 產品銷售而言，基於目前表現以及我們對第四季的預期，我們預計將落在 42 億至 45 億美元區間的低端。在思考支撐該指引之假設的演變時，有兩個主要驅動因素值得強調。

First, while we remain confident in our commercial strategy and trends prescribing behaviors take time to change, our expanded efforts to grow the prescriber base are gaining traction but are not yet translating into demand at the pace that we anticipated. We are moving expeditiously to execute the strategy and are laser-focused on driving new starts. With that said, we believe it is prudent to assume no material top-line contribution from our field expansion in our 2026 outlook.

第一，雖然我們仍對商業策略充滿信心，且處方行為趨勢需要時間改變，但我們擴大處方醫師基礎的努力正逐步見效，然而尚未以我們原先預期的速度轉化為需求。我們正迅速推進策略執行，並高度聚焦於推動新啟用（new starts）。儘管如此，我們認為在 2026 年展望中，審慎起見應假設我們的前線團隊擴編不會對營收帶來實質的頂線貢獻。

Second, there are two additional factors impacting our expectation for Q4 demand. First, our outlook reflects a prudent view of potential Q4 ordering behavior as hospital customers await the final 340B rule. While the proposed rule would not become effective until January 1, 2027, our interactions with health systems over the last few months suggest that it could create Q4 ordering volatility as providers assess the implications for their economics and site-of-care choices.

第二，還有兩項額外因素影響我們對第四季需求的預期。首先，我們的展望反映了對第四季可能出現的訂購行為所採取的審慎看法，因為醫院客戶正等待最終版 340B 規則。雖然該擬議規則要到 2027 年 1 月 1 日才會生效，但我們過去幾個月與醫療體系的互動顯示，當醫療提供者評估其對經濟效益與照護場域（site-of-care）選擇的影響時，可能在第四季造成訂購波動。

Second, our outlook also reflects an expected impact for more restrictive first-line AMVUTTRA access in the Medicare Advantage portion of the market following a policy change at UnitedHealth that was implemented October 1. All that said, achieving $4.2 billion in total TTR revenues would represent nearly 70% growth versus last year or $1.7 billion in growth on a dollar basis. As we look beyond 2026, we remain confident in the underlying opportunity for our TTR franchise.

其次，我們的展望也反映了在 UnitedHealth 於 10 月 1 日實施政策變更後，市場中 Medicare Advantage 部分對 AMVUTTRA 作為第一線用藥的取得預期將更為受限所帶來的影響。綜合而言，若達成 TTR 總營收 42 億美元，將代表較去年成長近 70%，以金額計約增加 17 億美元。展望 2026 年之後，我們仍對 TTR 產品線的基本機會充滿信心。

At the same time, as I mentioned a moment ago, we expect the final 340B rule in the coming weeks and for this rule to formally go into effect on January 1. This would provide only a limited window between the effective date and the JP Morgan conference to observe how health systems are responding under the new framework.

同時，如我剛才提到的，我們預期最終版 340B 規則將在未來幾週公布，並於 1 月 1 日正式生效。這將使得在生效日與 JP Morgan 大會之間，只有有限的時間窗口可觀察醫療體系在新框架下的反應。

We will, therefore, not be provided in 2027 product revenue guidance at JP Morgan as in past years, and instead expect to do so in conjunction with our fourth quarter and full year 2026 results in mid-February. That additional time will allow us to incorporate a more informed view of any changes in ordering patterns and site of care behavior as we guide the year ahead. We will continue to provide preliminary fourth quarter and full year 2026 revenue at JP Morgan in January as has been our normal practice.

因此，我們將不會像過去幾年一樣在 JP Morgan 大會提供 2027 年產品營收指引，而是預期在 2 月中旬公布 2026 年第四季與全年結果時一併提供。多出的時間將使我們在對來年提供指引時，能納入對訂購模式與照護場域行為變化更充分的判斷。我們將如以往慣例，於 1 月在 JP Morgan 大會提供 2026 年第四季與全年營收的初步數字。

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

現在我把電話交回 Josh，由他協調問答環節。Josh？

Thank you, Jeff. We're now going to open the call for Q&A. To those of you dialed in, only ask you to limit yourself to one question each and then get back in the queue if you have additional questions. Operator, please open the call for Q&A.

謝謝你，Jeff。接下來我們將開放問答。對於撥入的各位，我們請每人僅限提一個問題；若還有其他問題，請回到隊列重新排隊。接線員，請開放問答。

(Operator Instructions)

（接線員指示）

Kostas Biliouris, Oppenheimer.

Kostas Biliouris，Oppenheimer。

Thanks for taking our question and congrats on all the progress. many updates here. Maybe I'll ask a question on types of changes. Some people were expecting more changes than the one you made. Can you maybe talk a little bit about potential other changes that you may have consider -- for example, changing the primary endpoint by adding different components to the composite. And the second part of the question, should we expect more changes, or this is perhaps the final version of the design?

謝謝讓我們提問，也恭喜你們取得的各項進展。這裡有很多更新。我想我會問一個關於變更類型的問題。有些人原本預期會有比你們所做的那一項更多的變更。你們能否談談可能曾考慮過的其他變更——例如，透過在複合終點中加入不同組成項目來調整主要終點。以及問題的第二部分，我們是否應該預期還會有更多變更，還是這可能已是設計的最終版本？

Thanks, Kostas. Maybe a couple of points there. Maybe just to reiterate, as we kind of look at what we expect nuclisiran to do, nothing has changed in terms of our expectations around the therapeutic hypothesis or the expectation around the added efficacy that we'll get on top of a stabilizer nor its effect as a monotherapy. And we've shown some of our clinical trial simulations that feed into that and our understanding of the biology.

謝謝你，Kostas。我想也許有幾點要說明。先重申一下，當我們回頭看我們預期 nuclisiran 會帶來的效果時，無論是在治療假說的預期，或是在穩定劑（stabilizer）基礎上可額外獲得的療效增益之預期，以及其作為單藥治療的效果方面，我們的預期都沒有改變。我們也展示了一些臨床試驗模擬結果，這些結果支撐了上述預期以及我們對其生物學機制的理解。

Second, I think, as I've tried to highlight, our belief is also that you have to get in early to treat these patients most effectively. Our study is designed to do that. And we've already, we think highlight why we think an all-cause mortality endpoint is particularly relevant in this disease as well as an event-driven endpoint.

第二點，我想如同我一直強調的，我們也相信必須在早期介入，才能最有效地治療這些病人。我們的研究設計就是為了做到這一點。而且我們也已經說明了，為什麼我們認為在這個疾病中，全因死亡率（all-cause mortality）終點特別相關，同時事件驅動（event-driven）的終點也同樣重要。

So the key elements of the study design, we believe in strongly. I think the change that we made today is as we, again, look at evolution in event rates in the background as this patient population is better and better treated and an earlier diagnosed. And so in that context, there's no changes to the assumptions around the effect of the drug.

因此，我們對研究設計的關鍵要素抱持高度信心。我認為我們今天所做的變更，是因為我們再次觀察到背景事件率的演變：隨著這個病人族群獲得越來越好的治療、且更早被診斷。在這樣的背景下，對於藥物效果的假設並沒有任何改變。

It's really just about making sure we have adequate events and adequate power to demonstrate the efficacy of the drug. And so that's why we've added these 500 patients. As I've noted in prior calls, we're in an active enrollment period. And so we think that we can accrue these patients quite quickly. and we continue to further enrich for patients who are going to have the greatest benefit. So I think that's the study.

這主要是為了確保我們有足夠的事件數與足夠的統計檢定力（power）來證明藥物的療效。因此我們新增了這 500 名病人。如我在先前的電話會議中提到的，我們正處於積極收案期。所以我們認為可以相當快速地納入這些病人。同時我們也會持續進一步富集（enrich）那些最可能獲得最大受益的病人。我想這就是本研究的情況。

Now as it relates to analytic changes, this is an event-driven study. As we say, we project this to launch in 2030. So we have several years to kind of look and follow the patient population, event rates, et cetera, over the course of the study in a blinded fashion. And as we've done in the past, if there are any tweaks or adjustments to the analytic plan, those can be made at a later date. And so again, we are very vigilant and diligent on this study. It's very important, and we're committed to ensuring its success. But that's really the rationale and the thinking here.

至於分析層面的變更，這是一項事件驅動的研究。如我們所說，我們預計在 2030 年讀出結果。因此在研究期間，我們有好幾年時間可以在盲態（blinded）下持續觀察並追蹤病人族群、事件率等。而且如同過去的做法，如果分析計畫需要任何微調或調整，也可以在較後期再進行。所以再次強調，我們對這項研究非常警覺且嚴謹。這非常重要，我們也承諾確保其成功。以上就是這次調整的理由與思考。

Eli Merrell, Barclays.

Eli Merrell，巴克萊（Barclays）。

And just to elaborate a little bit on what you're seeing in some of the ATTR-CM commercial dynamics. You said that the expanded field force has increased physician engagement, but that hasn't turned into capacitor demand growth yet.

我想再請你們多談一點你們在 ATTR-CM 商業動態上看到的情況。你們提到擴編的業務團隊提高了醫師互動，但這還沒有轉化為 capacitor 需求的成長。

Can you elaborate a bit on that dynamic and why you think that is translating and maybe what hurdles might be affecting this? And strategies you can use to sort of grow this going forward? Is this mainly a lag issue? And I guess what feedback are you getting from some of these prescriber growth efforts?

你們能否更詳細說明一下這個動態，以及為什麼你們認為它會（或尚未）轉化？也許有哪些障礙正在影響？以及你們接下來可以採取哪些策略來推動成長？這主要是時間落後（lag）問題嗎？另外，你們從這些處方醫師拓展工作的回饋中，聽到的是什麼？

Thanks, Eddie. That's a great question. As I said, look, we're not satisfied with the pace of future demand growth, and we need to do better. That being said, we have delivered substantial growth since the launch. It's early days, and we think we significant opportunity ahead of us, and we've built a very strong foundation.

謝謝你，Eddie。這是個很好的問題。如我所說，我們對未來需求成長的速度並不滿意，我們需要做得更好。不過，我們自上市以來確實已交付了可觀的成長。目前仍在早期階段，我們認為前方仍有很大的機會，而且我們已建立非常扎實的基礎。

And all the market fundamentals remain favorable. As we said on our Q3 call, really, the key insight is the one-third of prescriber who's used AMVUTTRA. They use AMVUTTRA, they get experience, they prefer it. And that's across centers of excellence and the community. And that's the reason why we expanded the field force to address the two-third of prescribers who have yet to use AMVUTTRA to drive the next wave of growth in the launch.

而且市場的基本面仍然有利。如我們在第三季電話會議中所說，關鍵洞見在於：已有三分之一的處方醫師使用過 AMVUTTRA；他們一旦使用、累積經驗後，就會偏好 AMVUTTRA。這在卓越中心（centers of excellence）與社區端（community）皆是如此。這也是我們擴編業務團隊的原因：去觸及尚未使用 AMVUTTRA 的另外三分之二處方醫師，推動上市後的下一波成長。

And as we reflect on performance to date, we're pleased that reach and engagement are increasing. As Tolga said, we've now got 2,000 active prescribers of AMVUTTRA. And that's a good metric. The converting into patient starts is taking longer than we'd hoped. And we believe this is because of the expand the prescriber base.

回顧目前為止的表現，我們很高興看到觸及率與互動度正在提升。如 Tolga 所說，我們現在已有 2,000 位 AMVUTTRA 的活躍處方醫師，這是一個不錯的指標。但把這些互動轉化為病人起始用藥（patient starts）所花的時間比我們希望的更久。我們認為這是因為我們正在擴大處方醫師基礎。

Many of the newer physicians, they've got a few automopathy patients. They've got less understanding of the disease and more entrenched prescribing behaviors, that take time and sustained effort to change. And so we are increasing the intensity interactions to overcome any perceived barriers to AMVUTTRA. And really, what we need to do is build familiarity to drive adoption. There's physicians who are familiar with AMVUTTRA prefer it.

許多較新的醫師手上只有少數自體肌病（automopathy）病人。他們對疾病的理解較少，而且既有的處方行為更根深蒂固，改變需要時間與持續投入。因此我們正在提高互動強度，以克服對 AMVUTTRA 的任何既定疑慮；我們真正需要做的是建立熟悉度以推動採用。醫師一旦熟悉 AMVUTTRA，就會偏好它。

So we're very confident that we've made the right investments, and this is the right strategy, and we're focused on driving execution with urgency. It's going to take a little bit of time, we don't expect acceleration of growth in Q4 2026, but we're absolutely laser-like focused on ensuring that we can translate the additional engagements that we have with physicians and convert that into increased patient demand.

所以我們非常有信心，我們做了正確的投資、採取了正確的策略；我們也正以緊迫感聚焦於落地執行。這會需要一點時間；我們不預期 2026 年第四季成長會加速，但我們會非常聚焦，確保能把與醫師增加的互動，轉化為更高的病人需求。

Tolga, maybe you can talk about some of the very specific things that we're hearing from prescribers.

Tolga，也許你可以談談我們從處方醫師那裡聽到的一些非常具體的回饋。

Yes. So you covered the sort of the clinical piece, while maybe I can focus on the nonclinical barriers that we see. There are perceived beliefs that always is going to be easy for us to navigate the buy and build. How am I going to manage the patient coordination if I need to refer them to a site of care outside of my office. How is my staff going to be clearing the prior authorization.

好的。你已經涵蓋了臨床面的部分；我可以聚焦在我們看到的非臨床障礙。有一些既定看法認為，對我們來說要去處理採購與建置（buy and build）總是很容易。如果我需要把病人轉介到診所外的照護地點（site of care），我要如何管理病人協調？我的團隊要如何完成事前授權（prior authorization）的核准？

Now when we look at these actual nonclinical barriers, the good news is, as Yvonne indicated, half of our actual patient base is coming from community centers. And early on, those community centers had very similar perceptions. Once they've actually experienced our services and once the patient experience AMVUTTRA, we've been actually able to overcome that. Now the enemy here is the time. And it does take a number of frequent visits to make sure that we can actually bring those patients and physician offices along with that.

當我們檢視這些實際的非臨床障礙時，好消息是，如 Yvonne 所指出，我們實際病人基礎中有一半來自社區中心。而在早期，這些社區中心也有非常類似的看法。一旦他們實際體驗過我們的服務、且病人實際使用 AMVUTTRA，我們就能克服這些問題。但這裡的敵人是時間。確實需要多次且頻繁的拜訪，才能確保我們能把這些病人與醫師診所一起帶上來。

But once that happens, we've actually seen all these barriers that I just highlighted is eased out than the experience, obviously, biggest preference. So again, as Yvonne indicated, we're pleased but not satisfied with the progress that we made, and we do believe that we have the right Strategy to be able to open up those new accounts.

但一旦做到之後，我們確實看到我剛才強調的這些障礙會隨著經驗而逐步消除，而最終的偏好也會非常明顯。所以再次呼應 Yvonne 的說法，我們對已取得的進展感到欣慰，但仍不滿足；我們也相信我們有正確的策略，能夠開拓這些新客戶（accounts）。

Paul Matteis, Stifel.

Paul Matteis，Stifel。

Thank you for taking my question. I appreciate it. I know that there's probably some reluctance on speculating on the 340B rule change until it's finalized. But as you guys contemplate the impact right now, is this impact, if it does go through in its current iteration, confined to a hit to net price or do you also think that it could actually disrupt demand, both on the new start side or even on the actual existing patient side and drive patient switches is the reimbursement paradigm becomes more complicated or less attractive at the 340B institutions? Thank you.

謝謝讓我提問。我很感謝。我知道在 340B 規則變更尚未定案前，大家可能不太願意推測。但就你們目前評估其影響而言，如果它以目前版本通過，這個影響是否僅限於淨價（net price）受到衝擊？還是你們也認為它可能實際擾動需求——不論是新起始用藥端，甚至既有病人端——並在 340B 機構端因報銷（reimbursement）模式變得更複雜或吸引力下降，而驅動病人轉換用藥？謝謝。

Paul, this is Jeff. Thanks for the question. Yes, I understand the question, we did lay out a framework for how we're thinking about this. I think our focus right now is we're waiting for the rule to be finalized is really focused on patient access. And ensuring that the institutions, the 340B institutions and health systems that are treating these patients today will continue to have an economically viable option to do that in the future.

Paul，我是Jeff。謝謝你的提問。是的，我理解這個問題；我們確實已經提出一個框架，說明我們如何思考這件事。我認為我們目前的重點是，在等待規則定案的同時，真正聚焦於病患可近性（patient access）。並確保目前正在治療這些病患的機構——也就是340B機構與醫療體系——未來仍能以具經濟可行性的方式持續提供治療。

We laid out on the slide and Tolga mentioned in the script a couple of options that we'll have to support that. One would be contracting with the health systems, again, to ensure that there's an economically viable path for them to treat these patients. And then for health systems that they determine that they want to move the patients outside the health system, we have alternate sites of care. And this is actually one of the things that I think we've done very well since the launch that would support that, things like third-party infusion clinics things like getting the patients treated at home.

我們在投影片上已經列出，Tolga也在講稿中提到，我們將有幾個選項來支持這點。其中一個是與醫療體系簽訂合約，再次確保他們在治療這些病患時有一條具經濟可行性的路徑。另外，對於那些判定希望把病患移出其醫療體系的醫療體系，我們也有替代照護場域（alternate sites of care）。而這其實是我認為我們自上市以來做得非常好的一件事，可用來支持這點，例如第三方輸注診所，以及讓病患在家中接受治療等。

I think to your question, I think it's very difficult for us to predict the potential impact here. I think until we finalize the rule, and actually, we get some experience next year when we see the choices that the health systems are going to make. There could be impacts on gross to nets, either positive or negative based on the choices they make. And there could be impact on volume. We don't know that yet. Our belief is that the choices that physicians are making today in terms of how they treat their patients is primarily based on clinical decisions and what's going to be the best care for their patients.

我想回到你的問題，我認為我們很難預測這裡可能的影響。我認為要等到規則定案，而且實際上明年我們看到醫療體系將做出哪些選擇後，才會更清楚。總收入到淨收入（gross-to-net）可能會受到影響，依其選擇不同，可能是正面或負面。也可能會對銷量（volume）造成影響。我們目前還不知道。我們的看法是，醫師目前在如何治療病患方面所做的選擇，主要是基於臨床決策，以及什麼對病患而言是最佳照護。

We see that if you look across health systems today, these 340B institutions, we see different market share for AMVUTTRA across different health systems that reflects that. And I think even within an existing health system, if you look across different positions within that same health system, you see different utilization of AMVUTTRA. So we do think it's primarily going to be driven based on physician and patient choice on what they think is the best product for them going forward given the progressive and fatal nature of this disease.

我們看到，如果你觀察目前各醫療體系、這些340B機構，你會發現AMVUTTRA在不同醫療體系之間的市占率不同，這也反映了上述情況。而且我認為即使在同一個既有醫療體系內，如果你看同一體系中不同醫師，你也會看到AMVUTTRA的使用情況不同。因此我們確實認為，未來主要仍將由醫師與病患基於他們認為最適合的產品所做的選擇所驅動，尤其考量到此疾病具進行性且致命的特性。

Salveen Richter, Goldman Sachs.

Salveen Richter，高盛（Goldman Sachs）。

Thanks. Good morning here. So as we think about your 2027 outlook for the TTR franchise, it seems like there's a couple of moving parts, one being the demand growth via your commercial investments, but then also 340B reform. If it does pass at the proposed discount, recognizing you don't understand the likely impact here. Can you just help us kind of frame this around quantifying both your 340B exposure fee-for-service. But then also, are you allowed to bypass 340B with your own discounts, even if a covered entity?

謝謝。各位早安。因此，當我們思考你們對TTR產品線（franchise）在2027年的展望時，似乎有幾個變動因素：一個是透過你們的商業投資帶動的需求成長，但另一個則是340B改革。如果它以提案中的折扣幅度通過，並且理解你們目前也不清楚可能的影響。你能否協助我們從量化角度來框架這件事：你們在340B按服務計費（fee-for-service）方面的曝險有多大？另外，即使是受涵蓋實體（covered entity），你們是否可以用自有折扣來繞過340B？

Yes, I'll take this one. Thanks for the question. I think in terms of 340B in our business, it's a meaningful portion of our business. We're not going to get more explicit about it today. But that's why we're very focused on this and ensuring that we're coming up with solutions to ensure that the institutions that treat these patients have the ability to continue to do so in an economically viable manner.

好的，這題我來回答。謝謝你的提問。我認為就340B在我們業務中的占比而言，它是我們業務中相當有意義的一部分。我們今天不會對此提供更明確的細節。但也正因如此，我們非常專注於此，並確保我們提出解決方案，使治療這些病患的機構能夠以具經濟可行性的方式持續提供治療。

The second part of the question Bypass look, Yes. We listed options here in terms of options that we'll have to work with these institutions to ensure that they continue to have the ability to put patients on therapy, keep patients on therapy. And we talked about two options. One would be contracting and the second would be enabling alternate sites of care. Ultimately, the health systems themselves are then going to have to make choices about how they purchase the product.

至於問題的第二部分——繞過（bypass）——你看，是的。我們在這裡列出了幾個選項，作為我們與這些機構合作的方式，以確保他們仍有能力讓病患開始治療、並讓病患持續接受治療。我們談到兩個選項。一個是簽約（contracting），第二個是啟用替代照護場域（alternate sites of care）。最終，醫療體系本身將必須就如何採購產品做出選擇。

And if they want to keep the patients within their existing system, they'll likely have two options. One would be continuing in the 340B channel. Now the economics of that are going to change, but we think we have the ability to ensure that it stays an economically viable path for them. And then the second option would be if they want non-340B purchasing that could shift to WACC purchasing, which is also likely to be an economically viable path for them. if they choose not to continue to treat the patients within their health system, they also have options to move the patients outside of the system in terms of where they get access to the medicine.

如果他們希望讓病患留在其既有體系內，他們很可能有兩個選項。第一個是繼續走340B通路。當然其經濟性會改變，但我們認為我們有能力確保這對他們而言仍是一條具經濟可行性的路徑。第二個選項是，如果他們希望採用非340B採購，可能會轉向WACC採購（以批發採購成本為基礎），這也很可能對他們而言同樣是具經濟可行性的路徑。如果他們選擇不在其醫療體系內繼續治療病患，他們也有選項可將病患移到體系外，以取得藥物治療。

And that would be third-party infusion clinics, again, which we've done a very good job establishing 2,000 third-party clinics, 90% of patients within 10 miles of one of those clinics or to treat the patient in the home. So those are the options, I think, that are going to be at play here. And again, I think the good news is that those will -- if the systems want to continue to treat patients and add patients, they'll be able to do that.

那會是第三方輸注診所——同樣地，我們在建立這方面做得非常好：已建立2,000家第三方診所，90%的病患在距離其中一家診所10英里範圍內——或是在家中治療病患。所以我認為，這些就是在此情境下會發揮作用的選項。而且再次強調，好消息是：如果醫療體系希望持續治療病患並新增病患，他們將能夠做到。

Thanks, Jeff, and we're actively engaging with health systems so that we're ready to respond when the proposal is finalized and infant.

謝謝，Jeff。我們也正積極與醫療體系互動，以便在提案定案並生效時做好回應準備。

Whitney Ijem, Canaccord Genuity.

Whitney Ijem，Canaccord Genuity。

Hey, guys. Thanks for taking the question. I'm just going to ask a pipeline on timing. I guess, can you talk about what drove the delay of the HHT obesity data, which is now expected instead with fourth quarter earnings as opposed to before in year-end this year. And I guess remind us of what each data set will include and in particular, if that's changed with the delay.

嗨，各位。謝謝讓我提問。我想問一個關於研發管線時程（pipeline timing）的问题。我想，你們能否談談是什麼原因導致HHT肥胖數據延後？目前預期改為在第四季財報（earnings）時公布，而不是今年年底前。另外也請提醒我們每一組數據集會包含哪些內容，特別是延後之後內容是否有變動。

Thanks, Whitney. Maybe just to put a little context , there's been really no change in our overall timelines for either of those studies. They're still reading out. The studies are progressing well. They're on schedule, et cetera.

謝謝你，Whitney。也許先補充一點背景：我們對這兩項研究的整體時程其實沒有任何改變。它們仍會讀出（reading out）。研究進展良好。一切按計畫進行，等等。

They just are coming in at the end of the year, consistent with our goals. And so the next time for us to report those publicly will be in our Q4 year-end call. And so that's really what you're hearing there. So now in terms of the content for ALN-2232, that's our ACVR1c program for obesity and weight management. That's going to be our first adipose targeting program.

只是它們會在年底時點出來，與我們的目標一致。因此，我們下一次對外公開報告這些結果的時間，將是在我們第四季年終法說（Q4 year-end call）。所以你聽到的主要就是這個意思。至於ALN-2232的內容，那是我們針對肥胖與體重管理的ACVR1c計畫。那將是我們第一個以脂肪組織為標的（adipose targeting）的計畫。

And so we're looking forward to hopefully showing that as we sort of proceed along our goals to expand delivery to many tissues by 2030, that we can actually deliver safely and deeply into adipose tissue with good durability. And we'll be looking for primarily knockdown in safety data, but we will have some data in terms of biometrics in terms of weight and visceral fat, et cetera. We, again, particularly see this as an agent that can reduce visceral fat while maintaining muscle mass.

因此，隨著我們朝著2030年前將遞送（delivery）擴展到多種組織的目標推進，我們很期待能展示：我們確實可以安全且深度地遞送到脂肪組織，並具備良好的持久性（durability）。我們主要會關注敲低（knockdown）與安全性數據，但也會有一些生物測量（biometrics）方面的數據，例如體重與內臟脂肪等。我們同樣特別認為，這是一個能在維持肌肉量的同時降低內臟脂肪的藥物。

For ALN-6400 we'll have some Phase 1 data later this year at ASH, but we have this in the Phase 2 program in HHT. And we expect to have some initial proof-of-concept data and safety data. So efficacy and safety data that will present early next year. So those are the key highlights of the data that are coming out.

關於 ALN-6400，我們今年稍晚會在 ASH 看到一些第一期數據，但我們也已在 HHT 的第二期計畫中推進。我們預期會取得一些初步的概念驗證數據與安全性數據。因此，療效與安全性數據將於明年初發表。以上就是即將公布數據的重點摘要。

Thanks, Pushil. Good progress with our pipeline.

謝謝你，Pushil。我們的產品線進展良好。

Joon Lee, UBS.

UBS 的 Joon Lee。

Hi. Thanks for taking our questions. Really enjoyed your webinar on the Huntington's program. What are some key events in the space you're looking for to help you guide clinical development? And remind us, would it be a BLA or NDA. And a quick follow-up. Do you have any thoughts on developing a transparent receptor conjugated sRNA for CNS indications based on the evolving competitive landscape?

嗨，謝謝你們回答我們的問題。我非常喜歡你們關於亨丁頓氏症計畫的線上研討會。在這個領域中，你們正在關注哪些關鍵事件，以協助指引臨床開發？另外提醒我們一下，會是走 BLA 還是 NDA？再追問一個。基於競爭態勢的演變，你們對於為中樞神經系統（CNS）適應症開發透明受體（transparent receptor）偶聯的 sRNA 有什麼想法嗎？

Yes. Thanks for the question. The Brazil strand program is one that we're really, really excited about. And it really highlights the potential that we believe we have with our RNAi platform to make a deep and meaningful impact on really some of the most devastating diseases, Huntington's disease being one of them. So the data that we announced show that we really now have a differentiated approach to knock down that we can deliver deep knockdown.

是的，謝謝你的提問。Brazil strand 計畫是我們非常、非常興奮的一個項目。它也凸顯了我們相信 RNAi 平台所具備的潛力，能在一些最具破壞性的疾病上帶來深遠且有意義的影響，而亨丁頓氏症就是其中之一。我們公布的數據顯示，我們現在確實擁有一個具差異化的抑制策略，能夠達到深度的 knockdown（下調）。

We believe based on our preclinical and clinical data that we're getting good by distribution that we can target, not just the full length but also the shorter HTT-1a isoform and that we've been able to do so with good safety and tolerability to date. So as I noted, we're going to move forward into a Phase 3 program. The key things that we're looking for we are continuing to do dose escalation in our Phase 1. So we, again, want to maintain and ensure deep knockdown throughout the brain, including the deeper structures in the code. We want to ensure good durability and good tolerability.

我們根據目前取得的臨床前與臨床數據認為，我們在分佈方面表現良好，因此不僅能鎖定全長（full length），也能鎖定較短的 HTT-1a 異構體（isoform），而且迄今為止在安全性與耐受性方面也做到了良好表現。因此如我所提到的，我們將推進到第三期計畫。我們正在關注的關鍵事項是：我們在第一期試驗中持續進行劑量遞增。所以我們同樣希望維持並確保整個大腦（包括更深部的結構）都能達到深度 knockdown。我們也希望確保良好的持久性與良好的耐受性。

So we're continuing to do some further dose exploration in the Phase 1. As I've noted, those patients will transition into an open-label extension. As we get a little bit more, we firm up the doses and go through the regulatory process, we'll kick off that Phase 3 study that I noted in my prepared remarks. This will be an NDA program. All of our RNAi therapeutics are captured that way.

因此我們在第一期中持續做進一步的劑量探索。如我所提到，這些患者將轉入開放標籤延伸試驗。當我們取得更多資料、把劑量更明確地定下來並完成法規流程後，我們就會啟動我在事先準備講稿中提到的第三期研究。這將是一個 NDA 計畫。我們所有的 RNAi 治療藥物都是以這種方式納入。

As far as your last question, which is around a TFR based approach, we are very excited about what we have at hand. We think efficacy and safety are the most important things. And we don't see the current intrathecal approach as at all a barrier in this disease with this infrequent administration that we anticipate. But we are continuing to progress internally as part of our research efforts to explore ways to have a brain shuttle that can deliver peripherally. And so those activities are underway, and we'll update on that as well in the not-so-distant future.

至於你最後一個問題，也就是關於以 TFR 為基礎的方法，我們對手上所擁有的技術非常興奮。我們認為療效與安全性是最重要的。而且我們不認為目前的鞘內（intrathecal）給藥方式在這個疾病上會構成任何障礙，因為我們預期給藥頻率會很低。不過，我們也在內部持續推進研究工作，探索能夠以周邊給藥方式遞送的 brain shuttle（腦部穿梭載體）。因此這些工作正在進行中，我們也會在不久的將來就此更新進展。

Next question, please.

請下一個問題。

Ritu Baral, Cowen.

Cowen 的 Ritu Baral。

Good morning, guys. Another question for Pushkal on TRITON. Pushkal, how will you be further amending reducing the severity of patients enrolled in TRITON. And can you talk to how you might enrich them just beyond proBNP? And can you talk about the impact on powering of the 500 -- of the new 500 patients that you're going to be rolling and how much of a lower event rate are you calculating for in that powering?

各位早安。我還有一個關於 TRITON、想問 Pushkal 的問題。Pushkal，你們將如何進一步修訂，以降低 TRITON 入組患者的嚴重程度？另外，除了 proBNP 之外，你們能談談如何進一步做富集（enrich）嗎？也請談談對於你們將要入組的新 500 名患者，在統計把握度（powering）上的影響，以及在這個把握度計算中，你們假設事件率會降低多少？

Actually, that's like eight questions. Now I get the gist of what you're asking. Look, I think maybe two main elements, I think, that are in there. One is how are we adjusting for severity. I think the HELIOS SPEED data, the cardio transform data all indicate that if you can get into these patients early before they have presumably, we hypothesize a lot of built-up amyloid in the heart, which then becomes harder to modify and is going to lead to ongoing cardiovascular events.

其實這大概有八個問題。不過我理解你在問什麼。我想裡面大概有兩個主要要素。第一個是我們如何針對嚴重程度做調整。我認為 HELIOS SPEED 的數據、cardio transform 的數據都顯示，如果能在這些患者較早期介入、在他們心臟中推測（我們的假設）尚未累積大量類澱粉蛋白（amyloid）之前介入，因為一旦累積很多就更難以改變，並且會導致持續的心血管事件。

With this getting it earlier before that accumulates is where we're seeing the largest treatment effects. And we're seeing very substantial treatment effects in those earlier populations we were seeing upwards of 40% reduction in cardiovascular event rates. So and I think if you looked at the subgroup analysis of cardio transform despite the lower knockdown that, that drug was happening despite the fact that it doesn't din its primary endpoint in that subgroup of patients with earlier disease you were seeing a greater benefit. And that earlier disease population is often defined by NAC stage, which really is heavily weighted based on NT-proBNP. And so our study has entry criteria for NT-proBNP that can ensure we enroll patients who, a, are likely to have underlying disease and are likely experience events, but are not so advanced and we believe somewhat earlier in the disease course.

在累積之前更早介入，是我們看到最大治療效果的地方。而在那些較早期的人群中，我們看到非常顯著的治療效果，心血管事件率的降低幅度可達 40% 以上。此外，如果你看 cardio transform 的亞組分析，儘管該藥物的 knockdown 較低、而且它在該亞組中也未達到主要終點，但在疾病較早期的患者中，你仍然看到更大的獲益。而這個較早期的疾病族群通常以 NAC 分期來界定，而 NAC 分期在很大程度上是以 NT-proBNP 為主要權重。因此，我們研究的 NT-proBNP 入組標準可以確保我們納入的患者：a）很可能有潛在疾病，且很可能會發生事件；但又不至於太晚期，我們認為屬於疾病進程中相對較早的階段。

-- consistent with the principles I just laid out. So that's really the primary factor. There are other entry criteria in terms of history of events, et cetera. But I think that really, we believe, is an important driver in terms of stratifying a population, identifying the high risk and appropriate to treat most appropriate to treat patients. So that's that.

——這與我剛才闡述的原則一致。所以這確實是主要因素。另外還有其他入組標準，例如既往事件史等等。但我認為我們相信這一點在分層族群、辨識高風險、以及找出最適合治療的患者方面，是一個重要的驅動因素。以上是第一部分。

And in terms of the underlying event rates, I'm not going to get into any of the details of that. But I guess what I would like to assure you is that we've always been quite conservative in terms of our underlying trial assumptions. And again, the main thing is a secular trend towards these patients experiencing lower cardiovascular event rates because they're being diagnosed earlier and they're being treated more aggressively, particularly with SGLT2 inhibitors. And so we've taken that into account. And so we believe that with these 500 patients, 2,250 patients that we're now well positioned and well powered even under conservative assumptions of event rates. And so we'll follow those patients going forward.

至於基礎事件率，我不會深入任何細節。但我想向你保證的是，我們在試驗的基礎假設上一直都相當保守。而且，主要的因素是長期趨勢（secular trend）：這些患者的心血管事件率正在下降，因為他們被更早診斷，且治療更積極，特別是使用 SGLT2 抑制劑。因此我們已將這點納入考量。所以我們相信，以目前這 500 名患者、總計 2,250 名患者的規模，即使在保守的事件率假設下，我們也處於良好位置且具備足夠的統計把握度。因此我們會在後續持續追蹤這些患者。

David Lebowitz, BMO Capital Markets.

BMO Capital Markets 的 David Lebowitz。

Thank you very much for taking my question. Appreciating that you don't know details on 340B. As we look at our models and try to at least back into what potential impacts could be. What parts of the model should we consider looking at on both the top and bottom line side that could be impacted by the new regulation?

非常感謝讓我提問。我理解你們並不清楚 340B 的細節。但當我們檢視模型、並嘗試至少推算出新規可能帶來的影響時，在模型中有哪些部分（無論是營收端或獲利端）是我們應該考慮、可能會受到新規影響的？

Yes. Thanks for the question, Dave. It's Jeff. I mean I think there are two potential implications. One would be the price. And if you look at the slide, that we have in the deck on 340B and you look at the potential provider responses because ultimately, it's really going to be dictated by the choices that they make. But if the provider stay in the traditional 340B purchasing channel, that would increase gross to net, move net price down because we would be providing a discount below the current statutory 340B rate.

是的，謝謝你的問題，Dave。我是 Jeff。我認為可能有兩個影響。第一個是價格。如果你看我們簡報中關於 340B 的那張投影片，並看看潛在的醫療提供者（provider）反應，因為最終其實會由他們所做的選擇來決定。但如果醫療提供者仍留在傳統的 340B 採購通路，那將會提高 gross-to-net，使淨價下降，因為我們將提供低於目前法定 340B 比率的折扣。

However, if health systems move to WAC purchasing that moves out of the 340B channel, and that's positive to net price. And lastly, on that slide, if they move the patients out of the health system out of the 340B health system to an alternate site of care, that would also be positive from a net price perspective for us. I can't tell you exactly the choices they're going to make or what that's ultimately going to mean, but that gives you a sense of direction.

不過，如果醫療體系改採以 WAC（批發採購成本）進行採購、且因此移出 340B 通路，這對淨價格是正面的。最後，就那張投影片而言，如果他們把病人從 340B 醫療體系轉移到其他照護場域，從我們的淨價格角度來看也會是正面的。我無法確切告訴你他們會做出哪些選擇，或最終會代表什麼，但這能讓你了解大致方向。

And there was a prior question about impact on volume. Again, I can't predict that at this point either. We do think that physicians and patients are making choices based on what's the best product for their care in a progressive fatal disease. So we're going to wait and see how things play out with the rules we understand it and then get some experience with it in January before we provide more color on our year-end call in February.

另外先前也有人問到對用量的影響。同樣地，我目前也無法預測。我們確實認為，在這種進展性且致命的疾病中，醫師與病人會基於對其照護而言「最好的產品」來做選擇。因此，我們會先觀察在我們所理解的規則下事情如何發展，並在一月先累積一些實際經驗，之後再於二月的年終電話會議上提供更多說明。

Luca Issi, RBC Capital Markets.

Luca Issi，RBC Capital Markets。

Oh, great. Thanks so much for taking my question. Maybe, Jeff, appreciate you're not going to guide 2027 today and I appreciate you're not going to guide Egypt and Morgan as well. Can I maybe check your temperature on how you're thinking more broadly about your guided 25% plus total revenue CAGR throughout year-end.

喔，太好了。非常感謝讓我提問。Jeff，也許我可以這樣問：我理解你今天不會提供 2027 年的指引，我也理解你不會對 Egypt 和 Morgan 提供指引。我能否請你談談，你更廣泛地如何看待你們所指引的、到年終為止 25% 以上的總營收 CAGR（年複合成長率）？

Obviously, that guide was put forward before you recognize the second-line bolus before you recognize the 340B CMS proposal before this restricted Medicare Advantage change in policy by United. So should we think that, that 25% plus total revenue CAGR throughout 2030 is at this point a little bit on the optimistic side? Or do you still stand by that number? Again, any color there, much appreciated.

顯然，這項指引是在你們認列第二線 bolus（推注）之前、在你們認列 340B 的 CMS 提案之前、以及在 United 針對受限的 Medicare Advantage 政策變更之前提出的。所以我們是否應該認為，到 2030 年為止 25% 以上的總營收 CAGR，現階段看起來有點偏樂觀？還是你們仍然維持這個數字？再次感謝，若能提供任何補充說明將不勝感激。

Yes. No, thank you because that's really in our Alnylam sort of 2030 question and just kind of stepping back a little bit. I just want to say that I think we're making kind of really good progress, just nine months into the year across all the dimensions of online 2030. The AMVUTTRA launch is still early. We see significant opportunity ahead, and we're investing against that to broaden the prescriber base.

是的。不，謝謝你，因為這確實是我們 Alnylam 的「2030」相關問題，我先稍微退一步來看。我想先說，我認為我們在今年前九個月、在「Alnylam 2030」的各個面向都取得了相當不錯的進展。AMVUTTRA 的上市仍在早期階段。我們看到前方有顯著的機會，並且正投入資源以擴大開立處方的醫師基礎。

We're advancing nucrisiran. As Pushkal described, we have a lot of conviction in the study that we're progressing with Triton CM to extend the franchise. And we're building a pipeline which is progressing very well to deliver new medicines beyond TTR. With respect to the 25% CAGR, I think our confidence is really underpinned by the strong foundation we've built. And by the continued market growth that we see and robust market share, we expect that to be in the US treated ATTR cardiomyopathy population. We think that's going to grow and reach about 75,000 patients by 2030.

我們正在推進 nucrisiran。如 Pushkal 所描述，我們對正在推進的 Triton CM 研究非常有信心，藉此延伸我們的產品版圖（franchise）。同時，我們也在建立一條進展非常良好的研發管線，以在 TTR 之外帶來新的藥物。就 25% 的 CAGR 而言，我認為我們的信心確實是建立在我們所打造的強大基礎之上。此外，基於我們所看到的持續市場成長與穩健的市占率，我們預期這將反映在美國已治療的 ATTR 心肌病變族群。我們認為該族群將成長，並在 2030 年達到約 75,000 名病人。

And in the US, we're really looking to get one-third of the category TRx. And if we get there, we'll achieve our ambitions, and we're already there with NBRx. With TRx, we're now at 24% as we shared today, we're making meaningful progress. So kind of in summary, if we can capture one-third of the market in the US. with our current pricing assumptions and continue to grow, we haven't talked very much about ex US, it can continue to grow XES, we believe we're well positioned. And of course, we're going to be navigating near-term demand as well as the evolving payer environment.

在美國，我們的目標是取得該類別處方總量（TRx）的三分之一。若能達成，我們就能實現我們的目標；而在新處方（NBRx）方面，我們已經達到該水準。就 TRx 而言，如同我們今天分享的，我們目前為 24%，並且正在取得實質進展。因此總結來說，如果我們能在美國以目前的定價假設取得三分之一的市場並持續成長——我們對美國以外（ex US）談得不多——XES 也能持續成長，我們相信自身處於有利位置。當然，我們也將同時因應短期需求以及不斷演變的支付方環境。

So I believe that is our last question. So look, I'd just like to close by thanking everyone for joining us today. And I'd like to return to the patients that we have the opportunity to reach and the key priorities that will take us there. So the first thing that we need to do is convert the AMVUTTRA opportunity into more patient starts. We've had an exceptional first 18 months in ATTR cardiomyopathy, but it's early. So we need to continue to act with a laser-like focus to broaden the prescriber base, and we're going to continue to invest behind AMVUTTRA as a foundational therapy in this growing market.

我相信這是我們最後一個問題。那麼，我想在結束前感謝各位今天的參與。我也想回到我們有機會觸及的病人，以及能帶領我們達成目標的關鍵優先事項。第一件我們需要做的事，是把 AMVUTTRA 的機會轉化為更多病人開始治療（patient starts）。我們在 ATTR 心肌病變領域的前 18 個月表現非常出色，但仍屬早期。因此，我們需要持續以雷射般的專注來擴大開立處方的醫師基礎，並將持續加大對 AMVUTTRA 的投資，使其成為這個成長中市場的基礎治療。

And of course, the second is we need to build and sustain our leadership in TTR and TRITON-CM is central to that ambition and the expansion we announced today is intended to make an already well-designed study, as Pushkal described, even more robust, without changing our expected launch timing.

當然，第二點是我們需要建立並維持在 TTR 領域的領導地位，而 TRITON-CM 是實現該目標的核心；我們今天宣布的擴增，正如 Pushkal 所描述，旨在讓一項原本就設計良好的研究更為扎實，同時不改變我們預期的上市時程。

And then the third is advancing our pipeline. And you've heard the progress that we've made with Bassian to give us the opportunity to bring our science to new groups of patients, and we're very excited about moving forward in this regard. So together, these priorities drive our long-term 2030 ambition. And I'd like to finish by just thanking our employees of physicians, the investigators we work with and the patients and families who place their trust in what we do. Thank you for joining us today.

第三點則是推進我們的研發管線。各位也聽到我們在 Bassian 方面取得的進展，這讓我們有機會把我們的科學帶給新的病人族群；我們對於在這方面持續向前推進感到非常振奮。總而言之，這些優先事項共同推動我們 2030 年的長期目標。最後，我想感謝我們的員工、醫師、與我們合作的研究人員，以及信任我們所做工作的病人與家屬。感謝各位今天的參與。

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

今天的電話會議到此結束。感謝各位出席。您現在可以掛線。