Alnylam Pharmaceuticals Inc (ALNY) 2024 Q3 法說會逐字稿

Please stand by. Your program is about to begin. If you need assistance during your conference today, please press star zero.

請稍候。您的程式即將開始。如果您今天的會議期間需要協助，請按星號零。

Good day, everyone, and welcome to today's Alnylam Pharmaceuticals Q3 2024 Earnings Conference Call. At this time, all participants are in a listen-only-mode. Later, you will have the opportunity to ask questions during the question-and-answer session. (Operator Instructions)

大家好，歡迎參加今天的 Alnylam Pharmaceuticals 2024 年第三季財報電話會議。此時，所有參與者都處於只聽模式。稍後，您將有機會在問答環節提出問題。（操作員指令）

Please note this call is being recorded, and I will be standing by if you should need any assistance.

請注意，本次通話正在錄音，如果您需要任何協助，我將隨時待命。

It is now my pleasure to turn the conference over to the company.

現在我很高興將會議移交給公司。

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

早安.我是 Christine Lindenboom，Alnylam 首席企業傳播長。今天與我一起的是執行長 Yvonne Greenstreet； Tolga Tanguler，首席商務官； Pushkal Garg，首席醫療官；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.

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

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 and clinical progress, and Jeff will review financials and guidance, followed by a summary of upcoming milestones before we open the call for your questions.

在今天的電話會議中，正如幻燈片 2 中概述的那樣，Yvonne 將作介紹性發言並提供一些一般背景資訊。托爾加 (Tolga) 將提供有關我們全球商業進展的最新資訊。Pushkal 將審查管道更新和臨床進展，Jeff 將審查財務和指導，隨後總結即將到來的里程碑，然後我們再開始回答您的問題。

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.

我想提醒您，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》安全港條款所指的前瞻性陳述。

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. 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 obligation to update such statements.

由於各種重要因素，包括我們向美國證券交易委員會提交的最新定期報告中所討論的因素，實際結果可能與這些前瞻性陳述所示的結果有重大差異。此外，任何前瞻性陳述僅代表我們截至本紀錄日期的觀點，不應被視為代表我們在任何後續日期的觀點。我們明確否認有更新此類聲明的義務。

With that, I would like to turn the call over to Yvonne. Yvonne?

說到這裡，我想把電話轉給伊馮娜。伊馮？

Thanks, Christine, and thank you, everyone, for joining the call today. The third quarter of 2024 marked a period of continued progress for Alnylam on all fronts. Commercially, we achieved 34% year-over-year growth in global net product revenue, generating $420 million across our four marketed products.

謝謝，克里斯汀，也謝謝大家今天參加電話會議。2024 年第三季標誌著 Alnylam 在各方面持續進步的時期。從商業角度來看，我們的全球淨產品收入年增 34%，四種行銷產品的收入達到 4.2 億美元。

We made great progress with our TTR franchise, sharing additional results from the HELIOS-B study of vutrisiran and filing regulatory submissions in the US and EU. We also hosted a TTR Investor Day to highlight our preparations in anticipation of a potential launch in ATTR cardiomyopathy next year.

我們在 TTR 特許經營方面取得了巨大進展，分享了 HELIOS-B 對 vutrisiran 研究的更多結果，並向美國和歐盟提交了監管文件。我們也舉辦了 TTR 投資者日，重點介紹我們為明年可能在 ATTR 心肌病變領域推出產品所做的準備。

We believe that AMVUTTRA and our broader TTR portfolio will serve as our flagship franchise, similar and potential impact to what EYLEA has been for Regeneron or what the cystic fibrosis franchise has been for Vertex delivering to those companies durable growth and enabling those companies to invest in R&D, new product development and portfolio diversification for the long term.

我們相信，AMVUTTRA 和我們更廣泛的TTR 產品組合將成為我們的旗艦特許經營權，其潛在影響類似於EYLEA 對Regeneron 的作用，或囊性纖維化特許經營權對Vertex 的作用，為這些公司帶來持久成長，並使這些公司能夠投資於長期致力於研發、新產品開發和投資組合多樣化。

Lastly, our early pipeline saw continued momentum as well, particularly our efforts in CNS. We initiated a Phase 1 study of ALN-HTT02 in Huntington's disease, and we're pleased to announce today initial results from the multi-dose portion of the Phase 1 study of mivelsiran in patients with early onset Alzheimer's disease. These results are encouraging for our CNS platform as they provide early evidence that multiple doses of an intrathecally administered siRNA are well tolerated.

最後，我們早期的管道也持續保持強勁勢頭，特別是我們在中樞神經系統 (CNS) 領域的努力。我們啟動了 ALN-HTT02 治療亨廷頓舞蹈症的 1 期研究，今天我們很高興地宣布 mivelsiran 治療早發性阿茲海默症的 1 期研究多劑量部分的初步結果。這些結果對於我們的 CNS 平台來說是令人鼓舞的，因為它們提供了早期證據，證明鞘內注射多劑量 siRNA 具有良好的耐受性。

We're continuing to progress towards achievement by year-end 2025 of our Alnylam P5x25 goals and are steadfast in our belief that we're on track to become a top-tier biotech developing and ctransformative medicines for patients around the world with rare and prevalent diseases driven by a high-yielding pipeline of first and/or best-in-class product candidates from our organic product engine, all while delivering strong financial results.

我們將繼續朝著在 2025 年底實現 Alnylam P5x25 目標的目標邁進，並堅信我們正朝著成為頂級生物技術公司的方向發展，為全球患有罕見和流行疾病的患者開發和轉化藥物我們有機產品引擎中高收益的首創和/或一流候選產品線可有效治療多種疾病，同時帶來強勁的財務表現。

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

說完這些，現在我將把電話轉給托爾加 (Tolga)，讓他審查我們的商業表現。托爾加？

Thanks, Yvonne, and good morning, everyone. Q3 was another strong quarter for our commercial portfolio with our combined commercial portfolio delivering year-over-year growth of 34% compared with the third quarter of 2023 as we continue to consistently increase the number of patients on therapy in both our TTR and rare franchises.

謝謝，伊馮娜，大家早安。第三季度是我們商業投資組合表現強勁的又一個季度，與2023 年第三季度相比，我們的綜合商業投資組合同比增長34%，因為我們繼續持續增加TTR 和罕見特許經營中接受治療的患者數量。

Let me now turn to a summary of our third quarter TTR performance. Our TTR franchise achieved $309 million in global net product revenues, representing a 34% increase compared with the third quarter of 2023 as we continue to increase the number of hATTR polyneuropathy patients on our therapies, particularly noteworthy in the US given the competitive environment.

現在讓我來總結一下我們第三季的 TTR 表現。我們的TTR 特許經營權實現了3.09 億美元的全球淨產品收入，與2023 年第三季度相比增長了34%，因為我們繼續增加接受我們治療的hATTR 多發性神經病患者數量，考慮到競爭環境，這在美國尤其值得注意。

We are approaching 5,000 patients on treatment with ONPATTRO or AMVUTTRA globally, and there is still a significant growth opportunity given that our belief that 25,000 to 30,000 patients across the globe suffer from this devastating disease.

全球接受 ONPATTRO 或 AMVUTTRA 治療的患者已接近 5,000 名，而且我們認為全球有 25,000 至 30,000 名患者患有這種毀滅性疾病，因此仍有巨大的成長機會。

Now let me provide highlights of our US and Rest of World TTR performance. In the US, combined sales of ONPATTRO and AMVUTTRA increased by 8% compared with the second quarter and a robust 37% year-over-year as momentum in new patient adds continues to drive strong growth. The US 37% year-over-year growth was primarily driven by the following, a 31% increase in demand driven by the strength of ongoing AMVUTTRA patient uptake, more than offsetting the decrease in patients on ONPATTRO who have switched to AMVUTTRA. We are pleased with the growth in demand, which has been consistent throughout the year despite new competition entering the market at the end of 2023. Favorability is also driven by gross to net adjustment.

現在讓我介紹一下我們美國和世界其他地區 TTR 表現的亮點。在美國，由於新患者增加的勢頭繼續推動強勁增長，ONPATTRO 和 AMVUTTRA 的總銷售額與第二季度相比增長了 8%，與去年同期相比增長了 37%。美國年增 37% 主要得益於以下因素：由於 AMVUTTRA 患者持續強勁增長，需求增長 31%，遠遠抵消了使用 ONPATTRO 治療且改用 AMVUTTRA 的患者數量的減少。我們對需求的成長感到滿意，儘管 2023 年底出現了新的競爭對手，但需求全年一直保持穩定成長。總額與淨額的調整也推動了有利因素的出現。

Now let me turn to our international market, where the TTR franchise growth decreased by minus 9% compared to the second quarter of 2024, yet our quarter-over-quarter patient demand remains strong with plus 6% growth. The 9% quarter-on-quarter decrease was driven by a gross to net adjustment in Portugal that was booked in Q3 and large orders of ONPATTRO in our partner markets in Q2, including Australia, where we built inventory as we launched ONPATTRO in this market. On a year-over-year basis, the TTR business in international markets grew by 31% compared with the third quarter of 2023.

現在讓我來談談我們的國際市場，TTR 特許經營增長率與 2024 年第二季度相比下降了負 9%，但我們季度間患者需求仍然強勁，增長率為 6%。季減 9% 是由於第三季葡萄牙的毛利與淨利調整以及第二季我們在合作夥伴市場（包括澳洲）的大量 ONPATTRO 訂單，我們在澳洲市場推出 ONPATTRO 時累積了庫存。與去年同期相比，國際市場的TTR業務與2023年第三季相比成長了31%。

At our recent TTR Investor Day, we shared our plans for the promising potential of vutrisiran in addressing ATTR cardiomyopathy pending regulatory approval. We're confident in our journey towards leadership in this field, driven by several key factors.

在我們最近的 TTR 投資者日上，我們分享了在獲得監管部門批准後，vutrisiran 在治療 ATTR 心肌病變方面所具有的巨大潛力的計劃。在幾個關鍵因素的推動下，我們對成為該領域領導地位充滿信心。

ATTR cardiomyopathy is a rare and progressive disease where there is significant unmet need and substantial number of patients remain undiagnosed or not optimally treated. With HELIOS-B, we've shown very compelling results across key endpoints in a population reflective of today's patients.

ATTR 心肌病變是一種罕見且進行性疾病，存在嚴重未滿足的治療需求，大量患者未得到診斷或未得到最佳治療。透過 HELIOS-B，我們在反映當今患者群體的關鍵終點方面展示了非常令人信服的結果。

We have a track record of success in polyneuropathy and experience operating in a competitive environment. And our dedicated focus on ATTR will be instrumental as we scale for a successful launch, building Alnylam's flagship franchise and ushering a new phase of growth.

我們在多發性神經病變領域有著成功的記錄，並且在競爭環境中擁有豐富的營運經驗。我們對 ATTR 的專注將有助於我們擴大規模、成功發布、打造 Alnylam 的旗艦系列並迎來新的成長階段。

Now moving to our rare franchise and the performance of GIVLAARI and OXLUMO, which delivered $111 million in combined net product sales during the third quarter, representing an 8% increase compared with the second quarter of 2024 and 34% growth compared with the third quarter of 2023.

現在轉向我們的稀有特許經營權以及GIVLAARI 和OXLUMO 的表現，它們在第三季度實現了1.11 億美元的合併淨產品銷售額，與2024 年第二季度相比增長了8%，與2021 年第三季度相比成長了34%。

For GIVLAARI, Q3 product sales increased by 14% versus Q2, primarily due to the timing of orders in partner markets and a robust 31% compared with the third quarter of 2023 with the following year-over-year regional highlights. a 9% increase in the US, primarily driven by growth in new patients on therapy, a 79% increase in our rest of world markets, primarily driven by the timing of orders in our partner markets, primarily Brazil and increased demand growth across European markets.

對 GIVLAARI 而言，第三季產品銷售額較第二季成長 14%，這主要歸功於合作夥伴市場的訂單時機，以及與 2023 年第三季相比強勁成長 31% 以及隨後的同比區域亮點。美國市場成長 9%，主要得益於接受治療的新患者數量的成長；世界其他市場成長 79%，主要得益於我們合作夥伴市場（主要是巴西）的訂單時機以及歐洲市場的需求成長。

For OXLUMO, Q3 product sales were relatively flat versus Q2 2024, while delivering robust 40% year-over-year growth compared to Q3 2023 with the following regional dynamics, a 54% increase in the US, primarily driven by strong patient demand growth, a 33% growth from our rest of world markets, primarily driven by strong patient demand growth across both EU and our partner markets.

對於OXLUMO 而言，第三季產品銷售額與2024 年第二季相比相對持平，但與2023 年第三季相比實現了40% 的年成長，區域動態如下：美國成長54%，主要受患者需求強勁成長的推動，我們在世界其他市場的成長率為 33%，主要得益於歐盟和我們合作夥伴市場的患者需求強勁成長。

In conclusion, our third quarter results reflect consistent strength with both our TTR and rare franchises achieving impressive patient and revenue growth. This performance positions us well to meet the midpoint of our full year revenue guidance, which we updated and raised during our second quarter earnings call. We remain intensely focused on preparing for a potential ATTR cardiomyopathy launch next year.

總而言之，我們的第三季業績反映出持續的強勁勢頭，我們的 TTR 和稀有特許經營權均實現了令人矚目的患者和收入成長。這一業績使我們預計將達到全年收入預期的中位數，我們在第二季財報電話會議上更新並上調了這一預期。我們將繼續全力為明年潛在的 ATTR 心肌病變的推出做好準備。

And with that, I will now turn it over to Pushkal to review our recent R&D and pipeline progress. Pushkal?

現在，我將把時間交給 Pushkal 來回顧我們最近的研發和管道進展。普什卡爾？

Thanks, Tolga, and good morning, everyone. As you all know, Q3 was very exciting for our TTR franchise. We shared the full results from the pivotal HELIOS-B study at ESC in August and additional exploratory findings at HFSA in September. Together, these data presentations highlighted vutrisiran's potentially transformational profile in today's population of patients with ATTR cardiomyopathy with benefits across a comprehensive series of assessments.

謝謝，托爾加，大家早安。眾所周知，第三季對於我們的 TTR 特許經營來說非常令人興奮。我們在 8 月在 ESC 上分享了關鍵 HELIOS-B 研究的全部結果，並在 9 月在 HFSA 上分享了額外的探索性發現。總體而言，這些數據顯示強調了 vutrisiran 在當今 ATTR 心肌病變患者群體中的潛在變革性特徵，並透過一系列全面的評估帶來益處。

This started with rapid knockdown of TTR, characteristic of the RNAi mechanism of action. We then saw favorable impact on cardiac biomarkers as well as echocardiographic assessments, reflecting impact on the underlying pathophysiology of this disease.

這始於 TTR 的快速敲低，這是 RNAi 作用機制的特徵。然後，我們看到對心臟生物標記以及超音波心動圖評估的有利影響，反映了對該疾病潛在病理生理學的影響。

This was then followed by impact on a number of important clinical measures of function and health status, indicating delays in disease progression. And ultimately, we saw profound benefits on outcomes with a greater than 30% reduction in all-cause mortality.

隨後，一系列重要的臨床功能和健康狀況指標也受到影響，顯示疾病進展延遲。最終，我們看到了顯著的成果，全因死亡率降低了 30% 以上。

Based on these compelling data, we've now completed regulatory submissions in the United States, where we've used a priority review voucher and in the EU with additional global regulatory submissions to follow in late 2024.

基於這些令人信服的數據，我們目前已完成美國的監管提交，在美國我們使用了優先審查憑證，並在歐盟完成了其他全球監管提交，並將在 2024 年底完成。

Turning now to another important program for Alnylam. We're excited today to share new results from the multiple dose portion of the Phase 1 study of mivelsiran in patients with early onset Alzheimer's disease. As you recall, mivelsiran is a leading program in our effort to expand our RNAi platform to target organ systems beyond the liver and address the high unmet need that exists for neurologic diseases.

現在來談談 Alnylam 的另一個重要項目。今天，我們很高興與大家分享 mivelsiran 對早發性阿茲海默症患者進行治療的 1 期研究多劑量部分的新結果。您還記得，mivelsiran 是我們努力擴展 RNAi 平台以針對肝臟以外的器官系統並解決神經系統疾病尚未滿足的巨大需求的一個領先項目。

Mivelsiran is a C16 conjugated RNAi therapeutic targeting amyloid beta precursor protein or APP, and is in development for the treatment of Alzheimer's disease and cerebral amyloid angiopathy or CAA. APP is the upstream precursor of all amyloid beta peptides that form the amyloid deposits that are characteristic of these two diseases.

Mivelsiran 是一種針對澱粉樣β蛋白前體或 APP 的 C16 結合 RNAi 治療藥物，目前正在開髮用於治療阿茲海默症和腦澱粉樣血管病變或 CAA。APP 是所有澱粉樣β勝肽的上游前體，這些β肽形成了這兩種疾病特有的澱粉樣沉積物。

We believe that by lowering APP production, we can reduce the substrate for new amyloid deposition, potentially enable natural clearance and slow, halt or even improve the clinical manifestations of these devastating diseases.

我們相信，透過降低 APP 的產生，我們可以減少新的澱粉樣蛋白沉積的底物，潛在地實現自然清除，並減緩、停止甚至改善這些毀滅性疾病的臨床表現。

Today, we are sharing initial interim data from the first multiple dose cohort from the Phase 1 study of mivelsiran in early onset Alzheimer's disease patients. In the chart here in the dotted line, you can see the rapid, robust and sustained target engagement we achieved with a single 50-milligram dose during the single-dose part of the study as measured by the target engagement biomarker soluble APP beta.

今天，我們將分享 mivelsiran 治療早發性阿茲海默症患者第一階段研究的第一批多劑量組的初步中期數據。在此圖的虛線中，您可以看到，在研究的單劑量部分，我們透過單次50 毫克劑量實現了快速、穩定和持續的靶向作用，這透過靶向作用生物標誌物可溶性APP beta 來衡量。

After a single dose on day zero, mean reductions of approximately 75% in soluble APP beta were seen at month 1 with sustained reduction of approximately 50% still apparent at month 6 and a slow return towards baseline thereafter. In pink, you can see the initial interim data from the multiple dose portion of the study where patients were administered 50 milligrams at month zero and 6 and then followed through month seven or 30 days after that second dose.

在第零天單次給藥後，第 1 個月可溶性 APP β 平均減少約 75%，第 6 個月仍持續減少約 50%，此後緩慢恢復至基線。粉紅色部分是該研究多劑量部分的初始中期數據，其中患者在第 0 個月和第 6 個月接受 50 毫克治療，然後在第二次服用後的第 7 個月或 30 天進行隨訪。

You can see that APP beta follows a very similar trajectory to the patients after the single dose of 50 milligrams through the first six months. But then after the second 50-milligram dose at month 6, we see further reductions of APP beta at month 7, with patients achieving above 90% lowering of APP beta. So these are very encouraging data as they indicate we can achieve sustained robust lowering of APP with relatively low doses.

您可以看到，在前六個月內，APP beta 的變化軌跡與患者單次服用 50 毫克後的軌跡非常相似。但是，在第 6 個月第二次服用 50 毫克劑量後，我們在第 7 個月看到 APP β 進一步降低，患者的 APP β 降低了 90% 以上。因此，這些數據非常令人鼓舞，因為它們表明我們可以以相對較低的劑量實現 APP 的持續強勁降低。

Importantly, mivelsiran has been generally well tolerated in both the single and multiple dose parts of the study. No new safety signals have been identified in Phase 1 and no significant abnormalities have been seen on CSF safety labs such as total protein and CSF white cell count or on the exploratory biomarker neurofilament light chain.

重要的是，mivelsiran 在研究的單一劑量和多劑量部分都表現出良好的耐受性。在第 1 階段中沒有發現新的安全訊號，並且在 CSF 安全實驗室（例如總蛋白質和 CSF 白血球計數）或探索性生物標記神經絲輕鏈中沒有發現顯著異常。

Given these encouraging results, we continue to aggressively advance this program through clinical development. Specifically, we have continued dose escalation in the single ascending dose portion of the study to fully explore the safety and pharmacology profile of mivelsiran.

鑑於這些令人鼓舞的結果，我們將繼續透過臨床開發積極推進該計劃。具體來說，我們在研究的單次遞增劑量部分繼續增加劑量，以充分探索 mivelsiran 的安全性和藥理學特徵。

We've now also initiated multiple ascending dose cohort in the study to explore additional dose regimens. As we announced earlier this year, we've begun a Phase 2 study in CAA, the second leading cause of hemorrhagic stroke and for which there is no existing disease-modifying treatment.

我們現在也在研究中啟動了多個遞增劑量組，以探索額外的劑量方案。正如我們今年早些時候宣布的那樣，我們已經開始了 CAA 的 II 期研究，CAA 是出血性中風的第二大原因，目前尚無針對該疾病的治療方法。

And in parallel, we're defining next steps for a Phase 2 study in Alzheimer's disease and we'll provide updates in due course.

同時，我們正在確定阿茲海默症第二階段研究的後續步驟，並將在適當的時候提供最新消息。

Moving to another exciting pipeline update. We moved our third CNS program into the clinic with initiation of a Phase 1 study of ALN-HTT02, which targets the disease-causing Huntington protein in patients with Huntington's disease. In Q3, we shared nonclinical data supporting the broad CNS distribution as well as the tolerability of deep and sustained lowering of HTT in nonhuman primates after single and repeated intrathecal administration of ALN-HTT02.

轉向另一個令人興奮的管道更新。我們將第三個 CNS 計畫推向臨床，啟動 ALN-HTT02 的第一階段研究，該研究針對的是亨廷頓舞蹈症患者的致病亨廷頓蛋白。在第三季度，我們分享了非臨床數據，支持該藥物在中樞神經系統廣泛分佈，以及在非人靈長類動物中單次和重複鞘內注射ALN-HTT02 後深度和持續降低HTT 的耐受性。

We look forward to sharing updates on this exciting program in the future as we seek to address this progressive and fatal neurodegenerative disease.

我們期待在未來分享這項令人興奮的計劃的最新消息，以尋求治療這種漸進且致命的神經退化性疾病。

As we've discussed, our potential upcoming launch in ATTR cardiomyopathy, assuming regulatory approval and near-term achievement of sustainable profitability are going to give us a strong foundation to continue investing in the promise of RNAi therapeutics to treat a broad variety of diseases with critical unmet needs.

正如我們所討論的，假設獲得監管部門的批准和近期實現可持續盈利，我們即將推出的 ATTR 心肌病藥物將為我們繼續投資 RNAi 療法治療多種疾病奠定堅實的基礎。

But as we've also discussed, we continue to be disciplined about resource allocation in this key phase of growth. As part of that ongoing commitment to optimize our efforts, we've announced today a decision to stop clinical development of ALN-KHK, an investigational RNAi therapeutic targeting ketohexokinase for the treatment of type 2 diabetes mellitus.

但正如我們已經討論過的，在這個關鍵的成長階段，我們將繼續嚴格控制資源分配。作為持續優化努力承諾的一部分，我們今天宣布決定停止 ALN-KHK 的臨床開發，ALN-KHK 是一種針對酮己糖激酶的用於治療 2 型糖尿病的在研 RNAi 療法。

This decision furthers our efforts to allocate clinical, managerial and financial resources carefully to bring transformative medicines to patients, including our other programs in the metabolic space, which is an exciting one for RNAi therapeutics. We continue to explore multiple targets for metabolic disorders and look forward to sharing updates in the future.

這項決定進一步加強了我們精心分配臨床、管理和財政資源的努力，為患者帶來變革性藥物，包括我們在代謝領域的其他項目，這對 RNAi 療法來說是一個令人興奮的項目。我們將繼續探索代謝紊亂的多個目標，並期待將來分享最新消息。

So in sum, we've made great progress in advancing our pipeline and platform with much more to come. As a reminder, we're working towards filing proprietary INDs for nine programs by the end of 2025 against targets in the liver, CNS, muscle and adipose. If we include partnered programs, we anticipate the potential for 15 new INDs by the end of 2025, representing a near doubling of our clinical pipeline by the end of next year.

總而言之，我們在推進我們的管道和平台方面取得了巨大進展，未來還會取得更多進展。提醒一下，我們正致力於在 2025 年底之前為九個專案提交專有 IND，針對肝臟、中樞神經系統、肌肉和脂肪的目標。如果包括合作項目，我們預計到 2025 年底將有 15 個新的 IND，這意味著到明年年底我們的臨床管線將增加近一倍。

This remarkable and unique pace of innovation puts us in a great position to have a robust, self-sustainable pipeline that can deliver meaningful impact to patients across multiple disease areas.

這種卓越而獨特的創新步伐使我們處於有利地位，擁有強大而可自我維持的管道，可以為多個疾病領域的患者帶來有意義的影響。

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

現在，讓我將話題轉交給傑夫回顧我們的財務表現和即將到來的里程碑。傑夫？

Thanks, Pushkal, and good morning, everyone. I'm pleased to be presenting a summary of Alnylam's Q3 2024 financial results and discussing our full year guidance. Starting with a summary of our P&L results for Q3 2024 compared with the same period in 2023.

謝謝，普什卡爾，大家早安。我很高興能夠介紹 Alnylam 2024 年第三季的財務表現並討論我們的全年指引。首先，我們將 2024 年第三季的損益結果與 2023 年同期進行比較。

Total product revenue for the quarter was $420 million or 34% growth versus 2023, with both our TTR and rare franchises reporting strong growth of 34%, primarily driven by continued strong demand, as Tolga previously highlighted.

本季總產品收入為 4.2 億美元，較 2023 年增長 34%，其中我們的 TTR 和稀有特許經營權均報告 34% 的強勁增長，主要得益於持續強勁的需求，正如 Tolga 之前強調的那樣。

Net revenue from collaborations for the quarter was $57 million, representing a $370 million decrease when compared with last year. The decrease was primarily driven by the recognition in Q3 2023 of the $310 million upfront payment from Roche as well as the $65 million in revenue recognized from a $100 million milestone earned for achieving certain criteria during early clinical development for mivelsiran.

本季合作淨收入為 5,700 萬美元，較去年同期減少 3.7 億美元。下降的主要原因是 2023 年第三季確認了羅氏支付的 3.1 億美元預付款，以及在 mivelsiran 早期臨床開發期間因達到某些標準而獲得的 1 億美元里程碑所確認的 6500 萬美元收入。

Royalty revenue for the quarter was $23 million or more than double what was recognized in the third quarter of 2023. The increase was driven by higher Leqvio sales as Novartis continues to grow demand for Leqvio worldwide.

本季的特許權使用費收入為 2,300 萬美元，是 2023 年第三季營收的兩倍多。由於諾華在全球對 Leqvio 的需求持續增長，Leqvio 銷量的上升推動了這一增長。

Gross margin on product sales was 80% for the quarter compared with 75% in the third quarter of 2023. The improvement in margin is primarily due to higher costs in 2023 associated with canceled manufacturing commitments for ONPATTRO and other adjustments to inventory, for which similar expenses did not occur this year, offset by an increased rate of royalties payable on net sales of AMVUTTRA. I expect our gross margin on product sales will be lower in Q4, driven by a higher royalty rate payable on sales of AMVUTTRA.

本季產品銷售毛利率為 80%，而 2023 年第三季為 75%。利潤率的提高主要由於 2023 年取消 ONPATTRO 的製造承諾和其他庫存調整導致的成本增加，而今年沒有發生類似的費用，但 AMVUTTRA 淨銷售額應付特許權使用費的增加抵消了這一影響。我預計，由於 AMVUTTRA 銷售應付的專利稅率較高，我們第四季的產品銷售毛利率將會下降。

Our non-GAAP R&D expenses increased 12% in the third quarter compared to the same period last year, primarily due to increased costs associated with our preclinical activities as we progress our 225 strategy to expand our clinical pipeline by the end of 2025 as well as clinical activities, which mainly grew with expenses associated with zilebesiran KARDIA-3 Phase 2 clinical study and increased personnel costs.

與去年同期相比，我們的非 GAAP 研發費用在第三季度增長了 12%，這主要是由於我們推進 225 策略以在 2025 年底前擴大臨床管線，導致與臨床前活動相關的成本增加，以及臨床活動的成長主要源自於與zilebesiran KARDIA-3 第2 期臨床研究相關的費用以及人員成本的增加。

Our non-GAAP SG&A expenses increased 19% in the third quarter compared to the same period in 2023, primarily due to higher costs associated with marketing investments to promote our TTR therapies and preparations for the potential launch of AMVUTTRA for cardiomyopathy, along with increased personnel costs.

與2023 年同期相比，我們第三季度的非GAAP 銷售、一般及行政開支增長了19%，這主要是由於與推廣我們的TTR 療法的營銷投資相關的成本增加以及為可能推出用於治療心肌病的AMVUTTRA 做準備，以及人員增加成本。

Our non-GAAP operating loss for the quarter was $31 million, representing more than a $300 million decrease compared with Q3 2023, primarily driven by the recognition of collaboration revenue related to our Roche agreement and achievement of a mivelsiran milestone last year, as previously highlighted.

本季我們的非GAAP 營業虧損為3,100 萬美元，與2023 年第三季相比減少了3 億多美元，這主要是由於確認了與羅氏協議相關的合作收入以及去年實現了mivelsiran 里程碑，如前所述。

We ended the quarter with cash, cash equivalents and marketable securities of $2.8 billion compared with $2.4 billion as of December 31, 2023, with the increase primarily due to improved operating performance and net proceeds received from the issuance of common stock in connection with employee stock option exercises.

本季結束時，我們的現金、現金等價物和有價證券為28 億美元，而截至2023 年12 月31 日為24 億美元，增長主要由於經營業績改善以及與員工股票相關的普通股發行所得的淨收益選擇性執行。

Now I'd like to turn to our financial guidance for 2024. Today, we are reiterating our 2024 guidance that was updated on our Q2 earnings call. We anticipate combined net product revenues for our four commercial products will be within a range of $1.575 billion and $1.65 billion. Our collaboration and royalty revenue guidance range is $575 million to $650 million. And lastly, our guidance for combined non-GAAP R&D and SG&A expenses remains a range of between $1.775 billion and $1.875 billion.

現在，我想談談我們 2024 年的財務指引。今天，我們重申在第二季財報電話會議上更新的 2024 年指引。我們預計四種商業產品的綜合淨產品收入將在 15.75 億美元至 16.5 億美元之間。我們的合作和特許權使用費收入預期範圍為 5.75 億美元至 6.5 億美元。最後，我們對非 GAAP 研發和銷售、一般及行政費用總額的預期仍為 17.75 億美元至 18.75 億美元之間。

Let me now turn from financials and discuss some key goals and upcoming milestones for late 2024. We announced that we'll present additional findings from the ongoing Phase I study of ALN-TTRsc04 in patients with ATTR amyloidosis at the American Heart Association Scientific Sessions in November. We plan to share our Phase 3 development plan for ALN-TTRsc04 in the first quarter of 2025.

現在，讓我從財務角度轉而討論 2024 年末的一些關鍵目標和即將到來的里程碑。我們宣布，我們將於 11 月在美國心臟協會科學會議上展示更多正在進行的 ALN-TTRsc04 針對 ATTR 澱粉樣變性患者的 I 期研究的發現。我們計劃在 2025 年第一季分享 ALN-TTRsc04 的第三階段開發計畫。

We also intend to initiate a Phase 2 study for mivelsiran in patients with Alzheimer's disease at or around year-end.

我們也打算在年底或左右啟動針對阿茲海默症患者的 mivelsiran 第 2 階段研究。

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

現在讓我把話題轉回給克莉絲汀，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. Those dialed in, we would like to ask you to limit yourself to one question each and then get back in the queue if you have any additional questions.

謝謝你，傑夫。接線員，我們現在開始問答環節。對於那些撥打電話的人，我們希望你們將自己限制在每個問題上，然後如果你們還有其他問題，請回到隊列中。

Thank you. (Operator Instructions) And we'll take our first question from Ellie Merle with UBS. Your line is open.

謝謝。(操作員指示)我們將回答瑞銀的 Ellie Merle 提出的第一個問題。您的線路已開通。

Hey, guys. Thanks for taking the question. Just in terms of your earlier-stage pipeline, can you elaborate a bit on some of the work that you've done to improve the ability to deliver RNAi to adipose tissue and muscle? And how are you thinking about what makes the most sense as initial targets or diseases in these tissues? And any specific advantages to your approach versus other modalities? Thanks.

嘿，大家好。感謝您回答這個問題。就您早期的研發流程而言，您能否詳細闡述您為提高將 RNAi 遞送到脂肪組織和肌肉的能力所做的一些工作？您如何看待這些組織中最合理的初始目標或疾病？與其他方式相比，您的方法有什麼具體優勢嗎？謝謝。

Yes. Thanks, Ellie. As Jeff highlighted, we've talked about, we are very excited about the emerging profile of RNAi therapeutics, right? What we're seeing is that these therapies appear to be well tolerated, and we can get sustained knockdown of a disease-causing protein that allows for infrequent administration. And we're guided by human genetics in terms of the diseases that we pursue, which can allow us to validate both efficacy and safety using population genetics as well as preclinical work.

是的。謝謝，艾莉。正如 Jeff 所強調的那樣，我們已經討論過，我們對 RNAi 療法的新興概況感到非常興奮，對嗎？我們看到這些療法似乎耐受性良好，並且我們可以持續抑制致病蛋白質，從而實現不頻繁給藥。我們以人類遺傳學為指導來研究所研究的疾病，這使我們能夠利用群體遺傳學和臨床前工作來驗證其功效和安全性。

So adipose and muscle are two of the areas that we've highlighted in our 225 strategy as new tissues to pursue. We highlighted a little bit at R&D Day earlier in the year, some of the approaches that we're taking, and we remain on track to progress those. We actually are - we'll be talking about an R&D Day early next year, and we'll give the specific timing of that. And that's probably the best time for us to give a more substantive update on those programs.

因此，脂肪和肌肉是我們在 225 策略中重點關注的兩個新組織領域。我們在今年早些時候的研發日上重點介紹了我們正在採取的一些方法，並且我們仍在繼續進行這些方法。事實上，我們將在明年初討論研發日，並給予具體的時間。這可能是我們對這些計劃進行更實質更新的最佳時機。

But we're making good progress. And for competitive reasons, we're probably not going to say a lot more at this point.

但我們正在取得良好進展。出於競爭原因，我們目前可能不會透露太多。

Thanks, Pushkal. That's great. And I think it's one of the opportunities of our platform really is to continue delivering ongoing innovation as we start to make progress in some of these extrahepatic issues. Thank you, Ellie. Next question.

謝謝，普什卡爾。那太棒了。我認為這是我們平台的機會之一，實際上，當我們開始在一些肝外問題上取得進展時，我們將繼續進行創新。謝謝你，艾莉。下一個問題。

Gena Wang with Barclays.

巴克萊銀行的 Gena Wang。

Thank you for taking my questions. I wanted to ask one question regarding the ALN-HTT02. It seems like very impressive data in nonhuman primates. I believe this is one of very few showing actual knocking down in nonhuman primate brains instead of most of others showing rodent brain. So I know everyone is using 50% as a benchmark. Is that something you are looking for? What else you will be looking for regarding the Phase 1 data?

感謝您回答我的問題。我想問一個有關 ALN-HTT02 的問題。這似乎是非人類靈長類動物中非常令人印象深刻的數據。我相信這是極少數顯示非人類靈長類動物大腦中實際被敲除的病例之一，而不是大多數顯示囓齒動物大腦的病例。所以我知道大家都以 50% 作為基準。這是您要找的東西嗎？關於第一階段的數據您還希望了解什麼？

Yeah. Thanks, Gena. I'm glad you highlighted the Huntington's program because it's one that we're particularly excited about. This now represents our third CNS program that we're moving into the clinic. And what we're seeing here is that many of the insights that we learned from our APP program in terms of being able to have sustained knockdown of a disease-causing gene and appears to be well tolerated in preclinical studies is very encouraging.

是的。謝謝，吉娜。我很高興你強調了亨廷頓的項目，因為這是我們特別興奮的項目之一。這是我們目前進入臨床的第三個 CNS 項目。我們在這裡看到的是，我們從 APP 計劃中學到的許多見解，在能夠持續敲除致病基因方面，並且在臨床前研究中似乎具有良好的耐受性，這是非常令人鼓舞的。

So we believe we will have something that will allow sustained knockdown as well as hopefully be well tolerated in the clinic as we've seen with our APP program to date. The nonclinical findings were actually quite benign in the preclinical studies that we saw, as we highlighted in the slide, it was well tolerated both in rodent and nonhuman primate species.

因此，我們相信我們將擁有某種能夠持續敲除並且有望在臨床上獲得良好耐受性的東西，正如我們迄今為止在 APP 程序中看到的那樣。我們在臨床前研究中看到的非臨床發現實際上是相當良性的，正如我們在幻燈片中所強調的那樣，它在囓齒動物和非人類靈長類動物中都具有良好的耐受性。

And then the targeting approach we're taking is quite unique. We're going after an upstream portion of the gene, which includes the exon 1 fragment. And there's been an emerging amount of data in the literature that suggests that beyond targeting the full-length mutant protein that targeting the exon 1 fragment may also help in progression of this otherwise very, very rapidly progressive and fatal disease. So we think we may have an opportunity for unique efficacy with this molecule.

我們採取的定位方法非常獨特。我們正在追蹤該基因的上游部分，其中包括外顯子 1 片段。文獻中越來越多的數據表明，除了針對全長突變蛋白之外，針對外顯子 1 片段也可能有助於這種進展非常迅速且致命的疾病的進展。因此我們認為這種分子可能有機會發揮獨特的功效。

So we're moving forward in our single ascending dose study. These are in patients with symptomatic disease. We'll be looking at safety and tolerability, PK, PD, we'll be looking at changes in mutant Huntington's level - mutant Huntington levels. And we'll also have in that, as we go forward, clinical and imaging and biomarker measures, measures such as NfL, et cetera, that can be very useful in looking at progression in this disease.

因此，我們正在推進單次遞增劑量研究。這些都是有症狀疾病的患者。我們將關注安全性和耐受性、PK、PD，我們將關注突變型亨廷頓氏舞蹈症水平的變化 - 突變型亨廷頓氏舞蹈症水平。隨著研究的進展，我們還將進行臨床、影像和生物標記測量，例如 NfL 等測量，這些測量對於觀察這種疾病的進展非常有用。

The study is in active start-up mode in the UK Canada. And then in the United States, we also have a green light to proceed. I'll note that we do have a dose cap in the United States. And so we still have a green light to proceed in all three territories, and we're moving forward.

該研究在英國加拿大正處於積極啟動模式。在美國，我們也獲得了批准。我要指出的是，美國確實有劑量上限。因此，我們仍然有權在這三個地區開展業務，而且我們正在向前邁進。

So I'm very excited that we'll be able to do that. And we'll work with the FDA going forward if and when we need to sort of lift that dose cap. It may give us enough coverage as it is to cover the doses that we're interested in, but we'll work with the FDA in terms of lifting that dose cap over time. And so we're very excited about this program.

所以我很高興我們能夠做到這一點。如果我們需要取消劑量上限，我們將與 FDA 合作。它可能為我們提供足夠的覆蓋範圍以涵蓋我們感興趣的劑量，但我們將與 FDA 合作，隨著時間的推移取消劑量上限。因此我們對這個項目感到非常興奮。

Okay. Next question.

好的。下一個問題。

David Lebowitz with Citi.

花旗銀行的 David Lebowitz。

Thank you very much for taking my question. In terms of polyneuropathy at this point in time, how would you say the impact of a second silencer has been on the market and your overall trajectory? And additionally, I know that plenty of your prescribers for polyneuropathy are cardiologists. Have you noticed an inflection in the number of questions coming regarding the ATTR cardiomyopathy data?

非常感謝您回答我的問題。就目前的多發性神經病變而言，您認為第二個消音器對市場和整體發展軌跡有何影響？此外，我知道很多為您開立多發性神經病變處方的醫生都是心臟科醫生。您是否注意到有關 ATTR 心肌病變數據的問題數量有所變化？

Hi, Dave. Yeah. Look, I mean, now we have nine months under our belt with another competitor in the marketplace in the United States. And what you will see in our - both our quarter-over-quarter growth in the US, which is 8% up, as well as our year-over-year growth that is 37% up is a good indicative actually not only how this category still there's a significant unmet need, but how we've been able to actually compete versus a competitor.

你好，戴夫。是的。你看，我的意思是，現在我們與美國市場上的另一個競爭對手已經有九個月的合作經驗了。您將看到，我們在美國季度環比增長 8%，同比增長 37%，這不僅表明了這一點類別中仍然存在著巨大的未滿足需求，但我們如何才能真正與競爭對手競爭。

And we believe the fact that our route of administration is quarterly with a number of optionalities in terms of where those patients actually can receive their treatment. The fact that our patients remain on treatment due to this quarterly dosing and our patient services as well as, obviously, what you'll see in our platform that the ability to provide rapid knockdown as quickly as within the first dose at 60% and up to 88% after the second dose are important differentiators, and we believe this is really getting good traction, both with patients as well as physicians.

我們認為，我們的給藥方式是每季一次，在患者實際接受治療的地點方面有多種選擇。事實上，由於這種季度劑量給藥和我們的患者服務，我們的患者能夠繼續接受治療，而且顯然，您將在我們的平台上看到，能夠在第一次給藥時就提供60% 及以上的快速擊倒能力在第二次注射後達到 88% 是重要的區別因素，我們相信這對患者和醫生來說確實會產生良好的推動作用。

In terms of the cardiologists, the second part of your question, look, we've put established very clear guardrails to make sure that we are promoting compliantly and making sure that the launch is ahead of us, not - we're not in the launch phase. And when there is questions around HELIOS-B, we appropriately address that and triage that with our medical affairs colleagues.

至於心臟科醫生，你問題的第二部分，你看，我們已經建立了非常明確的護欄，以確保我們合規地推廣，並確保產品發佈在我們前面，而不是 - 我們不處於啟動階段。當有關 HELIOS-B 的問題出現時，我們會適當處理，並與我們的醫療事務同事進行分類。

But in terms of the number of patients that are coming in with that indication, that would not be something that we would allow as an organization. But overall, again, I'm very pleased with the performance of Q3, and we are seeing - we're continuing to see good robust demand in our polyneuropathy hereditary indication.

但就患有此種症狀的患者數量而言，我們作為一個組織是不會允許這種事情發生的。但總體而言，我對第三季度的表現非常滿意，而且我們看到 - 我們繼續看到多發性神經病變遺傳適應症的強勁需求。

That's terrific, Tolga. I think it illustrates that we've actually built a really high-performing commercial engine and we have a compelling profile for AMVUTTRA. So we're very excited about the future. Thank you. Next question.

太棒了，托爾加。我認為這表明我們實際上已經製造了一款性能極高的商用發動機，並且 AMVUTTRA 的形象十分引人注目。所以我們對未來感到非常興奮。謝謝。下一個問題。

Paul Matteis with Stifel.

Paul Matteis 和 Stifel 在一起。

Hi. Great. Thanks so much. I wanted to ask one more follow-up question just on recent prescribing dynamics in TTR in light of the HELIOS-B data. And Tolga, I totally understand where you're coming from, right, that you guys promote solely in polyneuropathy. But just as it relates to a cardiologist if they want to prescribe AMVUTTRA right now, what are the prior auth requirements that you see?

你好。偉大的。非常感謝。我想根據 HELIOS-B 數據再問一個關於 TTR 近期處方動態的後續問題。托爾加，我完全理解你的意思，對吧，你們只宣傳多發性神經病。但是，如果心臟科醫師現在想要開立 AMVUTTRA 處方，您認為需要哪些事先授權要求？

Do they need to have a neurologist offer corroboration of a polyneuropathy diagnosis? Like are there kind of significant impediments in place that really can find this drug to that true mixed phenotype population at this point before getting an expanded label? Thank you.

他們是否需要神經科醫師來證實多發性神經病變的診斷？例如，在獲得擴大標籤之前，是否存在重大障礙，導致這種藥物真的能夠適用於真正的混合表型群體？謝謝。

Yeah, Paul, that's a great question. And you clearly grasp some of the complications and how the patients are actually getting diagnosed. So if you're in a cardiomyopathy if you're suspected of having a cardiomyopathy, physicians, especially in the United States, tend to go through scintigraphy. And if the patient actually is determined to have the condition as suspected, they would then be quickly put on the treatment.

是的，保羅，這是一個很好的問題。而且您可以清楚地了解一些併發症以及患者的實際診斷方法。因此，如果您患有心肌病，或被懷疑患有心肌病，醫生（尤其是美國的醫生）往往會進行閃爍掃描檢查。如果確定患者確實患有疑似疾病，那麼就會迅速接受治療。

Now in polyneuropathy, not only because of our indication is hereditary that you would actually go to a genetic testing to validate that. And then you would also have an additional neurological workout to make sure that, that patient actually has the neurological manifestations of the disease and then you would be put on the treatment.

現在對於多發性神經病，不僅因為我們的指徵是遺傳性的，你實際上需要進行基因檢測來驗證這一點。然後您還需要進行額外的神經系統運動以確保患者確實具有該疾病的神經系統表現，然後才會接受治療。

Now in terms of the access challenges, nearly all of our patients actually end up getting good sustained access regardless of what source of reimbursement channel they have. So that's really not the challenge. It's mostly is - is the challenge on the diagnostic pathway, polyneuropathy hereditary being the last stage of that pathway rather than the first stage what we see in cardiomyopathy.

現在就獲取挑戰而言，無論患者擁有何種報銷管道，我們幾乎所有的患者最終都能獲得良好的持續獲取服務的機會。所以這真的不是一個挑戰。最主要的是 - 是診斷途徑上的挑戰，遺傳性多發性神經病變是該途徑的最後階段，而不是我們在心肌病變中看到的第一階段。

Ritu Baral with TD Cowen.

Ritu Baral 的 TD Cowen。

Hi, guys. Thanks for taking the question. I wanted to ask just how Tolga and maybe, Jeff, how you are thinking about payer discussions now even ahead of potential label expansion. What are the levers, what are the topics that you're discussing? And how are you viewing the potential for volume-based discounts upon potential label expansion and increasing number of patients on AMVUTTRA?

嗨，大家好。感謝您回答這個問題。我想問一下托爾加，也許還有傑夫，你們是如何考慮現在甚至在潛在的品牌擴張之前進行付款人討論的。槓桿是什麼？隨著 AMVUTTRA 藥品標籤擴展和患者數量的增加，您如何看待批量折扣的潛力？

That's a great question, Ritu. I think it's actually for Tolga.

這是一個很好的問題，Ritu。我認為它實際上是給托爾加 (Tolga) 的。

Yeah. So Ritu, as we shared at the TTR Day, what payers care as they should be is the value proposition, which is really driven by the clinical outcome. And as we have demonstrated in HELIOS-B, the product really does provide an incredible and important differentiator in terms of CV outcome in today's patient population.

是的。因此，Ritu，正如我們在 TTR 日所分享的那樣，付款人應該關心的是價值主張，而價值主張實際上是由臨床結果驅動的。正如我們在 HELIOS-B 中所展示的那樣，該產品確實在當今患者群體的心血管結果方面提供了令人難以置信的重要差異化因素。

So that's what we're so far seeing is payers understanding, acknowledging that this remains a rare, albeit growing disease and the fact that the HELIOS-B results outcomes are compelling. In terms of how we're going to be able to navigate the access landscape has a lot to do with our patient access philosophy.

所以到目前為止我們看到的是付款人的理解，承認這仍然是一種罕見的、儘管正在增長的疾病，並且 HELIOS-B 的結果令人信服。就我們如何能夠駕馭訪問環境而言，與我們的患者訪問理念有很大關係。

I think what we've been able to demonstrate within the polyneuropathy indication, how we've been able to get seamless access to our patients and a big majority of them not having any co-pay burden and about 30% of them end up having about $2,000 or less co-pay burden.

我認為，我們已經能夠在多發性神經病適應症中證明，我們如何能夠無縫地接觸我們的患者，他們中的大多數沒有任何共同支付負擔，大約 30% 的人最終約2,000 美元或更少的共同支付負擔。

And part of our patient access philosophy has to do with value-based agreements and appropriate rebates. This is an area where, obviously, we're going to be disclosing more. We understand and appreciate why there is interest in this. But we will actually communicate that as we get more closer to our PDUFA date, which is not set yet.

我們的患者可及理念的一部分與基於價值的協議和適當的回扣有關。顯然，我們將在這個領域披露更多資訊。我們理解並讚賞人們為什麼對此感興趣。但我們實際上會在接近 PDUFA 日期時進行溝通，但該日期尚未確定。

Got it. And let me ask very quick follow-up, guys, just on Paul's question. It's a follow-up to Paul's. So I'm going to squeeze this in. How is there how is the cardiologists and neurologists understanding of compressive neuropathies factor into Paul's question?

知道了。各位，讓我為保羅的問題做一個快速的跟進。這是對保羅的後續。所以我要把它擠進去。心臟科醫師和神經科醫師對壓迫性神經病變的理解如何影響保羅的問題？

You mean carpal tunnel or spinal.

您的意思是腕管或脊椎。

Carpal tunnel spinal stenosis. Yeah, in that.

腕管脊椎狹窄。是的，就那樣。

So I mean, yeah. Look, I mean, I think TTR is a systemic disease, and that's why you have multicenters that actually treat multidisciplinary physicians that actually treat this disease. Now this doesn't also, of course, exist in every market, every academic - even every academic center. But in most centers, you have a good collaboration between a cardiologist and a neurologist and in some cases, even orthopedic surgeon.

所以我的意思是，是的。看，我的意思是，我認為 TTR 是一種全身性疾病，這就是為什麼有多中心治療中心和多科醫生來治療這種疾病。當然，這種情況並不存在於每個市場、每個學術領域，甚至每個學術中心。但在大多數中心，心臟科醫生和神經科醫生之間有著良好的合作，在某些情況下，甚至還有骨科醫生。

But because the disease has been evolved, the genesis of the disease evolved by the cardiologists, the first stop tends to be the cardiologists where they actually do the scintigraphy and do the preliminary diagnosis. And if there is not suspicion of additional manifestations of disease, they tend to go with the only approved product that's available today. And we believe that's obviously going to change over time.

但因為這種疾病已經進化，這種疾病的起源是由心臟科醫生進化而來的，所以第一站往往是心臟科醫生，他們實際上在那裡做閃爍掃描並做初步診斷。如果沒有懷疑其他疾病表現，他們往往會選擇目前唯一核准的產品。我們相信，隨著時間的推移，這種情況顯然會改變。

I think it's a great question actually, Ritu, because these red flag symptoms, I think, are going to be an important part of physician education and awareness going forward. So thanks for the question. The two questions. Let's take the next question.

我認為這實際上是一個很好的問題，Ritu，因為我認為這些危險信號症狀將成為未來醫生教育和意識的重要組成部分。感謝您的提問。這兩個問題。我們來回答下一個問題。

Salveen Richter with Goldman Sachs.

高盛的 Salveen Richter。

Thanks for taking our question. This is Tommy on for Salveen. So you talked about how there is this initial focus on frontline for cardiomyopathy. But wondering if - what's your thoughts on if there could be a bolus of path progressors in the second half of next year who are aware and kind of want something new? Thank you.

感謝您回答我們的問題。這是 Salveen 的 Tommy。所以您談到了最初關注的是心肌病變的一線治療。但我想知道——您是否認為明年下半年可能會出現一群意識到這一點並且想要一些新事物的進步者？謝謝。

Yeah. I mean at our TTR Day, we delayered the strategy. And the reason why we explained that strategy has a lot to do with what the data suggests and where today's patients are. So as we've highlighted, this is a fast progressing and severe disease.

是的。我的意思是，在我們的 TTR 日，我們分層了策略。我們解釋該策略的原因與數據顯示的情況以及當今患者的狀況有很大關係。正如我們所強調的，這是一種進展迅速且嚴重的疾病。

So our understanding is the treaters are really focusing to make sure that they - as soon as they diagnose these patients, they want to diag them early and they want to hit hard, hit hard with a product that we believe is going to be providing data with today's patient population, where the subgroup patients where a portion of them are on the only stabilizers that is available or with GLP-1 or they are on diuretic intensification. Those are the patients that they are currently seeing.

因此，我們的理解是，治療人員真正關注的是確保他們——一旦他們診斷出這些患者，他們希望儘早診斷，並且他們希望用我們認為可以提供數據的產品來大力打擊。其中一部分亞組患者僅使用可用的穩定劑或GLP-1，或正在服用強化利尿劑。這些都是他們目前正在看診的病人。

And if you look at the dynamic of the market, we see ever larger number of patients that are coming into the category. So you want to be able to establish yourself as a first-line product because of the data and because of the fast progress of the nature of the disease, so those patients actually can get treated.

如果你觀察市場的動態，我們會發現越來越多的患者正在進入這個類別。因此，您希望能夠根據數據以及疾病性質的快速進展將自己確立為一線產品，以便那些患者實際上能夠得到治療。

Now in terms of patients that might be progressing on a stabilizer, of course, I'm sure physicians will start identifying those patients if they haven't already done so and we'll probably eventually either depending on the access limitations or challenges that they may have, either put them switch them on those patients or use a combination therapy.

現在，對於可能正在使用穩定劑的患者，我當然相信醫生會開始識別這些患者，如果他們還沒有這樣做的話，我們最終可能會根據他們所面臨的獲取限製或挑戰可能有，要么把它們用在這些病人身上，要嘛使用聯合療法。

Now it's important to highlight that until tafamidis will become generic, there is no switch behavior that's been established in this category. Therefore, we do believe that will take some time to establish. And obviously, we will be doing our part to make sure that those patients are identified, those patients that are progressing are well identified.

現在需要強調的是，在 Tafamidis 成為通用藥物之前，該類別中尚未建立任何轉換行為。因此，我們確實相信這需要一些時間來建立。顯然，我們將盡自己的責任確保這些患者能夠被識別，那些病情正在惡化的患者能夠被正確識別。

But I think it's important to highlight that given the number of patients that are coming into the category and the dynamic and the data that we have, we believe AMVUTTRA will be well positioned to become a first-line standard of care therapy.

但我認為，必須強調的是，考慮到進入該類別的患者數量以及我們擁有的動態和數據，我們相信 AMVUTTRA 將有能力成為第一線標準護理療法。

Thanks, Tolga.

謝謝，托爾加。

Assuming approval of --

假設批准--

Thank you for answering that question. Next question.

感謝您回答這個問題。下一個問題。

Jessica Fye with JPMorgan.

摩根大通的傑西卡·菲伊 (Jessica Fye)。

Hey, guys. Good morning. Thanks for taking my question. I got another one on TTR. Is there anything that you're going to be watching for in the acoramidis label with their PDUFA coming up? And I guess, stepping back, do you see any of the potential label scenarios for that product as relevant to your expectations for your own launch in TTR cardiomyopathy? Thank you.

嘿，大家好。早安.感謝您回答我的問題。我在 TTR 上又得到了一個。隨著 PDUFA 的出台，您會關注 acoramidis 標籤中的哪些內容？我想，退一步來說，您是否認為該產品的任何潛在標籤場景與您對 TTR 心肌病變產品推出的期望相關？謝謝。

Yeah. Look, like everybody, obviously, we're interested in seeing the acoramidis label assuming approval. I mean, we feel very confident about the data that we've generated with HELIOS-B. And we're looking forward actually to moving through the regulatory process in both the US and in Europe and using our priority review voucher, assuming a potential approval early next year. So we feel really good about where we are. And I think we'll just have to wait to see exactly what gets delivered with respect to acoramidis.

是的。看起來，像所有人一樣，我們顯然都希望看到 acoramidis 標籤獲得批准。我的意思是，我們對使用 HELIOS-B 產生的資料非常有信心。我們實際上期待通過美國和歐洲的監管程序並使用我們的優先審查憑證，假設明年年初可能獲得批准。所以我們對自己的現狀感到非常滿意。我認為我們只需要等待，就能看到關於 acoramidis 的具體交付情況。

Yeah. The only thing I would add is, obviously, to comment on their label would be speculative. But from a broader market dynamic perspective, we believe acoramidis will be a twice daily stabilizer. And how that market dynamic will shape, I think we'll have to do a lot to do with our orthogonal mechanism of action and how we would be able to compete in the patient population that are still, again, as a first-line agent or those patients that are progressing on a stabilizer.

是的。我唯一想補充的是，顯然，對他們的標籤進行評論只是推測而已。但從更廣泛的市場動態角度來看，我們認為 acoramidis 將成為每日兩次的穩定劑。至於市場動態將如何形成，我認為我們必須做很多工作來研究我們的正交作用機制，以及我們如何能夠在患者群體中競爭，而這些患者群體仍然是一線藥物或正在使用穩定劑的患者。

Terrific. Thank you. Next question please.

了不起。謝謝。請回答下一個問題。

Gary Nachman with Raymond James.

加里納赫曼和雷蒙德詹姆斯。

Thanks. Good morning. So as we anticipate the launches of vutri and ATTR-CM next year in both the US and then the EU, how should we think about spending levels in SG&A relative to this year for all the commercial activities you'll be doing, just order of magnitude?

謝謝。早安.因此，我們預計明年將在美國和歐盟推出 vutri 和 ATTR-CM，我們應該如何考慮相對於今年您將進行的所有商業活動的 SG&A 支出水平，只是順序如下震級？

And then remind us of the infrastructure you have in Europe and how you think of the CM opportunity there relative to the US in terms of both accessing patients and also pricing? Thanks.

然後請您提醒我們一下您在歐洲的基礎設施，以及您如何看待那裡相對於美國在獲取患者和定價方面的 CM 機會？謝謝。

That's a great question. Thank you. I think Jeff will take the first part of it, and then Tolga will follow up with his plans for making sure that we kind of execute on our plans for potential AMVUTTRA launch.

這是一個很好的問題。謝謝。我認為傑夫將負責第一部分，然後托爾加將跟進他的計劃，以確保我們能夠執行潛在 AMVUTTRA 發布的計劃。

Yeah. I mean, I would say we upgraded our guidance this year at Q2 on OpEx, right? And that reflected the confidence that we had in the HELIOS-B results and sort of playing to win. And so you'll see in the second half of the year this year an increase in investment. And the commercial team has made very good progress in starting to prepare for the launch, particularly in the US with the hiring that's been done.

是的。我的意思是，我想說我們在今年第二季上調了營運支出預期，對嗎？這體現了我們對 HELIOS-B 結果的信心以及爭取勝利的決心。因此你會看到今年下半年投資會增加。商業團隊在開始準備發布方面已經取得了非常好的進展，特別是在美國已經完成了招募。

So with a lot of that happening in the second half of the year, that's obviously going to create growth for next year. And we'll continue to invest more broadly even than just in the US as we move towards the second half of the year and launches in Europe. I don't have specific guidance, but I would expect that certainly double-digit growth in terms of SG&A. But we'll provide our annual guidance for '25 on our year-end call in February.

因此，隨著今年下半年出現大量此類事件，顯然將為明年帶來成長。隨著今年下半年我們進入歐洲市場，我們將繼續進行更廣泛的投資，甚至不僅限於美國。我沒有具體的指導，但我預期銷售、一般及行政開支肯定會達到兩位數的成長。但我們將在 2 月的年終電話會議上提供 25 年的年度指導。

Yeah. And what's been great is that we've actually built a very strong foundation actually in TTR polyneuropathy. And so really, it's been more of a sort of incremental growth to make sure that we're absolutely well positioned to be successful in the CM indication. But Tolga, anything else to...

是的。非常高興的是，我們實際上已經在 TTR 多發性神經病變領域建立了非常堅實的基礎。因此，實際上，這更像是一種漸進式成長，以確保我們在 CM 適應症方面處於絕對有利的成功位置。但是托爾加，還有什麼可以做的…

I mean, the only thing I would add is from an organizational focus perspective, we have established an end-to-end organization, which has actually demonstrated excellent results, not only in TTR, but also in rare. So our TTR organization, not only in Europe, but also in Japan, has been demonstrating really robust growth numbers. I mean we've just posted a 31% year-over-year growth. If you look at the performance of - on the demand side of our international business has been up at 6% quarter-over-quarter.

我的意思是，我唯一想補充的是，從組織重點的角度來看，我們已經建立了一個端到端的組織，它實際上已經顯示出優異的成績，不僅在TTR 中，而且在罕見方面也是如此。因此，我們的 TTR 組織不僅在歐洲，而且在日本都表現出了真正強勁的成長勢頭。我的意思是我們剛剛公佈了 31% 的同比增長。如果你看一下我們國際業務需求的表現，你會發現我們的國際業務較上季成長了 6%。

Now that's been done in a market where there is significant price sensitivity, where we have a PN product that's priced for the narrower indication. And we've been able to become a market leader at 80% versus tafamidis in that specific PN indication where we also compete with them in that indication.

現在，這已經在價格敏感度較高的市場中完成了，我們擁有針對較窄適應症定價的 PN 產品。並且，在該特定 PN 適應症中，我們以 80% 的價格領先 tafamidis，我們也在該適應症中與他們競爭。

So we actually are quite pleased with the structure that we've established and as Jeff indicated, we're going to play to win and make sure that we are providing the right access options in those markets. And so far, we've been able to compete well, and we believe we'll be able to do that with the HELIOS-B data as a tailwind.

因此，我們實際上對我們已經建立的結構感到非常滿意，正如傑夫所說，我們將盡全力爭取勝利，並確保我們在這些市場中提供正確的訪問選項。到目前為止，我們一直能夠保持良好的競爭力，我們相信，借助 HELIOS-B 數據，我們一定能夠做到這一點。

Great. Thank you, Tolga. Next question.

偉大的。謝謝你，托爾加。下一個問題。

Kostas Biliouris with BMO Capital.

BMO Capital 的 Kostas Biliouris。

Good morning, everyone. Thanks for and outside of your pipeline, acknowledging that your pipeline is large and very robust and can drive growth. I'm wondering whether you can comment on potential BD activities that could potentially support even additional growth in addition to your internal efforts? Thank you.

大家早安。感謝您以及您的管道之外的人，承認您的管道很大且非常強大，可以推動成長。我想知道您是否可以評論一下除了內部努力之外可能支持額外增長的潛在 BD 活動？謝謝。

Yeah. No, that's a great question. Look, we're very privileged actually to have kind of an incredibly rich pipeline. I mean we think it's one of the most exciting pipelines in the industry. And Pushkal touched on the fact that we'll be doubling the pipeline by the end of '25. So we've got a lot of really, really interesting opportunities in the company.

是的。不，這是一個很好的問題。瞧，我們非常榮幸能夠擁有如此豐富的管道。我的意思是我們認為這是業內最令人興奮的管道之一。普什卡爾提到，到 25 年底，我們將把管道數量增加一倍。因此，我們在公司裡有很多非常非常有趣的機會。

And clearly, we're also going to make sure that we focus on a successful AMVUTTRA launch. And so we're really focused on driving both our internal pipeline, as well as continuing to optimize the platform.

顯然，我們也將確保專注於 AMVUTTRA 的成功發布。因此，我們真正專注於推動內部管道發展以及繼續優化平台。

When we think about BD, we're also very open to considering opportunities that really enable our platform and help us continue to access all the other tissues, and Pushkal described some of these. And so really, that's our focus at the moment. Clearly, we obviously pay a lot of attention to what's happening in the innovation landscape around us. But really, we have - we're in a very privileged position to have an awful lot that we can progress within the company, and we're excited to move all of that forward.

當我們考慮 BD 時，我們也非常願意考慮真正支持我們的平台並幫助我們繼續訪問所有其他組織的機會，Pushkal 描述了其中的一些。所以這確實是我們目前的重點。顯然，我們非常關注周遭的創新格局。但實際上，我們處於非常有利的地位，可以在公司內部取得很大的進步，我們很高興能夠推動這一切向前發展。

Next question. I think this is our last question.

下一個問題。我想這是我們的最後一個問題。

We'll take our last question from Tazeen Ahmad with Bank of America.

我們將回答美國銀行的 Tazeen Ahmad 提出的最後一個問題。

Great. Thank you for squeezing me in. Maybe this last one is for Tolga going back to the launch. In terms of expectations, for the early part of any rare disease launch, I think companies talk about the time it's going to take from the time the script is written to the time that the script is dispensed to the patient.

偉大的。謝謝你擠進我。也許最後一個是為了讓托爾加重返發射場。就預期而言，對於任何罕見疾病藥物上市的早期階段，我認為公司會談論從寫好處方到將處方分發給患者所需的時間。

But since this is going to be the second indication for your product, do you expect those traditional sometimes conservative time lines as to extended time period, at least initially to hold true here? Or do you expect that to already have been smoothed out from your PN launch? Thanks.

但是，由於這是您產品的第二個適應症，您是否預計那些傳統的、有時保守的時間表至少在最初會在這裡適用？或者您期望從 PN 發布開始這個問題就已經解決？謝謝。

Yeah. Thank you, Tazeen. We recognize that this is an area where we do need to provide some additional color. And we will do that closer to our launch time lines and the respective engagements that we will have, and we should be able to provide additional context as we get closer to the launch.

是的。謝謝你，塔澤恩。我們認識到我們確實需要在這個領域提供一些額外的顏色。我們將在接近發佈時間表和相關活動時進行上述操作，並且我們應該能夠在接近發佈時提供更多背景資訊。

Thank you, Tolga. And look, thank you to everyone for joining us on the call. We feel very pleased with the third quarter of 2024. It was one of continued progress. We delivered robust financial growth as well as advancements in our pipeline. So thank you, everybody, and have a great day.

謝謝你，托爾加。感謝大家參加我們的電話會議。我們對 2024 年第三季感到非常滿意。這是一個持續進步的過程。我們實現了強勁的財務成長以及產品線的進步。謝謝大家，祝大家有個愉快的一天。

That concludes today's teleconference. Thank you for your participation. You may now disconnect.

今天的電話會議到此結束。感謝您的參與。您現在可以斷開連線。