Alnylam Pharmaceuticals Inc (ALNY) 2022 Q4 法說會逐字稿

Thank you for standing by, and welcome to the Alnylam Pharmaceuticals Fourth Quarter 2023 Financial Results Conference Call. As a reminder, today's conference call is being recorded. I would now like to hand the conference over to the company. Please go ahead.

感謝您的支持，歡迎來到 Alnylam Pharmaceuticals 2023 年第四季度財務業績電話會議。提醒一下，今天的電話會議正在錄製中。我現在想把會議交給公司。請繼續。

Good morning. I'm Christine Lindenboom, Senior Vice President of Investor Relations and Corporate Communications at Alnylam. With me today on the phone are: Yvonne Greenstreet, Chief Executive Officer; Tolga Tanguler, Chief Commercial Officer; Pushkal Garg, Chief Medical Officer; and Jeff Poulton, Chief Financial Officer.

早上好。我是 Christine Lindenboom，Alnylam 的投資者關係和企業傳播高級副總裁。今天和我通電話的有：首席執行官 Yvonne Greenstreet； Tolga Tanguler，首席商務官； Pushkal Garg，首席醫療官；和首席財務官 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.

對於那些通過電話會議參與的人，可以通過訪問我們網站 investors.alnylam.com/events 投資者頁面的活動部分來訪問隨附的幻燈片。

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

在今天的電話會議中，如幻燈片 2 中所述，Yvonne 將提供介紹性評論和一般背景。 Tolga 將提供我們全球商業進展的最新信息。 Pushkal 將審查管道更新和臨床進展，Jeff 將審查我們的財務和指導，然後是即將到來的里程碑的摘要，然後我們開始徵求您的問題。

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

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，這些評論構成針對 1995 年《私人證券訴訟改革法案》安全港條款的前瞻性陳述。實際結果可能存在重大差異由於各種重要因素，包括我們最近提交給美國證券交易委員會的定期報告中討論的因素，這些前瞻性陳述表明的那些。此外，任何前瞻性陳述僅代表我們截至本記錄之日的觀點，不應被視為代表我們截至任何後續日期的觀點。我們特別聲明不承擔任何更新此類聲明的義務。

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

有了這個，我想把電話轉給伊馮娜。伊馮？

Thanks, Christine, and thank you, everyone, for joining the call today. 2022 is an excellent year at Alnylam, where we delivered impressive commercial performance and made significant advancements across our broad pipeline of RNAi therapeutics. Commercially, as preannounced in January, we achieved full year 2022 net product revenues of $894 million, which represents year-over-year growth of 35%, or 43% with constant exchange rates, and 13% growth between the third and fourth quarters.

謝謝，克里斯汀，感謝大家今天加入電話會議。 2022 年對 Alnylam 來說是出色的一年，我們取得了令人印象深刻的商業業績，並在我們廣泛的 RNAi 療法管道中取得了重大進展。在商業上，正如 1 月份預先宣布的那樣，我們實現了 2022 年全年淨產品收入 8.94 億美元，同比增長 35%，按固定匯率計算增長 43%，第三季度和第四季度增長 13%。

A tailwind to the success was the approval and launch of AMVUTTRA in the U.S., Germany and Japan for hereditary ATTR amyloidosis patients with polyneuropathy, where rapid uptake among physicians and patients reflects its attractive product profile. With our pipeline, notable progress during the year included the exciting results for APOLLO-B, our Phase III study of patisiran for ATTR amyloidosis patients with cardiomyopathy. The sNDA based on these results has been accepted with a PDUFA date of October 8, and we look forward to the FDA's review and potential approval later this year. Pushkal will provide more color on this later in the call.

成功的一個推動因素是 AMVUTTRA 在美國、德國和日本的批准和上市，用於治療患有多發性神經病的遺傳性 ATTR 澱粉樣變性患者，醫生和患者的快速接受反映了其有吸引力的產品概況。憑藉我們的產品線，這一年取得的顯著進展包括 APOLLO-B 的令人興奮的結果，這是我們針對 ATTR 澱粉樣變性心肌病患者的 patisiran III 期研究。基於這些結果的 sNDA 已被接受，PDUFA 日期為 10 月 8 日，我們期待 FDA 在今年晚些時候進行審查和可能的批准。 Pushkal 將在稍後的通話中提供更多顏色。

Among our earlier programs, a highlight for the year was the initiation of the first human study of RNAi therapeutics for the CMS with ALN-APP for Alzheimer's disease. We also completed 3 CTA filings, advancing to the clinic promising programs such as ALN-KHK for type 2 diabetes, ALN-PNP for NASH and ALN-TTRsc04 for ATTR amyloidosis, and we're announcing today that dosing has started in a Phase I study with this program.

在我們早期的項目中，今年的一個亮點是啟動了第一個針對 CMS 的 RNAi 療法的人體研究，使用 ALN-APP 治療阿爾茨海默氏病。我們還完成了 3 份 CTA 申請，推進到臨床有前途的項目，例如用於 2 型糖尿病的 ALN-KHK、用於 NASH 的 ALN-PNP 和用於 ATTR 澱粉樣變性的 ALN-TTRsc04，我們今天宣布，劑量已經開始進入 I 期學習這個程序。

Looking forward to the rest of 2023, we're excited for several important pipeline milestones, including 10 clinical readouts from Alnylam and partner-led programs, such as Phase I results from the aforementioned ALN-APP study and Phase II results from the cardio-hypertension studies of zilebesiran. This execution is in line with our focus on the following key drivers for Alnylam's growth over the next several years.

展望 2023 年的剩餘時間，我們對幾個重要的管道里程碑感到興奮，包括來自 Alnylam 和合作夥伴主導的項目的 10 個臨床讀數，例如上述 ALN-APP 研究的 I 期結果和心臟- Zilebesiran 的高血壓研究。這一執行符合我們對 Alnylam 在未來幾年增長的以下關鍵驅動因素的關注。

First is the potential near-term expansion of our ATTR franchise opportunity, where we aim to become a global leader in delivering impactful and highly differentiated medicines to patients. Second is our expansion beyond rare diseases to also address more common disease areas. And the third growth driver for the company comes from our sustainable innovation engine, comprised of new platform enhancements, opportunities with extrahepatic delivery and our ability to find new genetically validated targets, which can drive further pipeline expansion to 2025 and beyond.

首先是我們 ATTR 特許經營機會的潛在近期擴張，我們的目標是成為向患者提供有影響力和高度差異化藥物的全球領導者。其次是我們將業務擴展到罕見病以外的領域，以解決更常見的疾病領域。公司的第三個增長動力來自我們的可持續創新引擎，包括新平台的增強、肝外交付的機會以及我們找到新的基因驗證目標的能力，這可以推動管道進一步擴展到 2025 年及以後。

We believe all of this positions us well to deliver on our Alnylam P5x25 goals, making Alnylam a top-tier biotech developing and commercializing transformative medicines for rare diseases and beyond for patients around the world, driven by a high-yielding pipeline of first and/or best-in-class product catheters from our organic product engine, all while delivering exceptional financial results.

我們相信，所有這些都使我們能夠很好地實現我們的 Alnylam P5x25 目標，使 Alnylam 成為頂級生物技術公司，在第一和 /或來自我們有機產品引擎的一流產品導管，同時提供卓越的財務業績。

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

有了這個，現在讓我把電話轉給托爾加，讓他審查我們的商業表現。托爾加？

Thanks, Yvonne, and good morning, everyone. Our commercial operations had a strong close to 2022, delivering $262 million in combined net product sales in Q4, which represented 13% growth compared with Q3 2022. The strong growth was driven by an increase in patients on commercial therapy across both our TTR and ultra-rare franchises. We remain particularly encouraged by several signs indicating that the ongoing launch of AMVUTTRA for hATTR amyloidosis patients with polyneuropathy, both in the U.S. and now also in Germany and Japan, is expanding the size of the opportunity for our TTR franchise.

謝謝，伊馮娜，大家早上好。我們的商業運營在接近 2022 年時表現強勁，第四季度的產品淨銷售額為 2.62 億美元，與 2022 年第三季度相比增長了 13%。強勁的增長是由我們的 TTR 和 ultra 商業治療患者的增加推動的- 罕見的特許經營權。我們仍然特別受到一些跡象的鼓舞，這些跡象表明，在美國以及現在在德國和日本，正在為患有多發性神經病的 hATTR 澱粉樣變性患者推出 AMVUTTRA 正在擴大我們 TTR 特許經營機會的規模。

Now I will turn to our specific results, starting with our TTR franchise. We saw robust growth in our TTR franchise in Q4, achieving $191 million in global net product revenues for ONPATTRO and AMVUTTRA, representing a 12% increase compared with the first quarter and a solid 38% growth compared with Q4 2021. The year-over-year growth in Q4 was driven by the strength of the AMVUTTRA launch in the U.S., with the U.S. market delivering an impressive 72% growth compared with Q4 2021.

現在我將轉向我們的具體結果，從我們的 TTR 特許經營權開始。我們在第四季度看到了 TTR 特許經營權的強勁增長，ONPATTRO 和 AMVUTTRA 的全球產品淨收入達到了 1.91 億美元，比第一季度增長了 12%，與 2021 年第四季度相比增長了 38%。第四季度的年度增長受到 AMVUTTRA 在美國推出的強勁推動，與 2021 年第四季度相比，美國市場實現了令人印象深刻的 72% 的增長。

At the end of 2022, over 2,975 patients were on commercial ONPATTRO or AMVUTTRA treatment worldwide, an increase of nearly 400 patients from the end of Q3, which represents a doubling of the quarterly trend that existed prior to the launch of AMVUTTRA, a clear signal of accelerating TTR franchise growth.

到 2022 年底，全球有超過 2,975 名患者接受了 ONPATTRO 或 AMVUTTRA 的商業治療，比第三季度末增加了近 400 名患者，這代表了 AMVUTTRA 推出之前存在的季度趨勢的兩倍，這是一個明確的信號加速 TTR 特許經營增長。

In the U.S., combined sales of ONPATTRO and AMVUTTRA increased 12% versus the third quarter and were primarily impacted by the following: a robust 19% increase in demand growth, which was driven by the strength of the AMVUTTRA patient uptake, which is being driven both by switches from ONPATTRO and, more importantly, from increases in patients new to therapy.

在美國，ONPATTRO 和 AMVUTTRA 的合併銷售額比第三季度增長了 12%，主要受到以下因素的影響：需求增長強勁增長 19%，這是由 AMVUTTRA 患者接受的力量推動的，這正在推動兩者都來自 ONPATTRO 的轉變，更重要的是，來自新接受治療的患者的增加。

ONPATTRO inventory destocking in the channel during the fourth quarter reduced reported TTR growth by approximately 5%. This was anticipated as demand for ONPATTRO in the U.S. continues to decrease as more patients switch to AMVUTTRA.

ONPATTRO 第四季度渠道庫存去庫存使報告的 TTR 增長降低了約 5%。這是預期的，因為隨著越來越多的患者轉向 AMVUTTRA，美國對 ONPATTRO 的需求持續下降。

In our international markets, combined sales of ONPATTRO and AMVUTTRA also increased 12% versus Q3 2022, primarily driven by the success of initial international AMVUTTRA launches in Germany and Japan, with growth favorably impacted both by increased patient demand and initial launch stocking.

在我們的國際市場上，ONPATTRO 和 AMVUTTRA 的合併銷售額也比 2022 年第三季度增長了 12%，這主要是受 AMVUTTRA 在德國和日本首次國際上市的成功推動，增長受到患者需求增加和首次上市庫存的有利影響。

Finally, our global results continue to be challenged by foreign exchange headwinds, with total TTR year-over-year reported growth of 38% reflected a foreign exchange impact of 10 percentage points due to the strengthening U.S. dollar.

最後，我們的全球業績繼續受到外匯逆風的挑戰，報告的總 TTR 同比增長 38% 反映了美元走強導致的 10 個百分點的外匯影響。

Now I would like to provide you with some additional color on our ongoing AMVUTTRA U.S. launch progress as well as an update on initial international launches in Germany and Japan. In the U.S., we received more than 750 AMVUTTRA start forms in the 6-plus months since launch, with more than 50% of the start forms representing new patients and the balance representing switches from ONPATTRO. Consistent with what we shared at Q3, the monthly average of new therapy AMVUTTRA start forms remains at 60 per month, which is double the rate of ONPATTRO, new-to-therapy start forms that we were receiving prior to the launch of AMVUTTRA.

現在，我想為您提供一些關於我們正在進行的 AMVUTTRA 美國發布進展的更多信息，以及在德國和日本首次國際發布的最新情況。在美國，我們在推出後的 6 個多月內收到了超過 750 份 AMVUTTRA 啟動表格，其中超過 50% 的啟動表格代表新患者，其餘代表來自 ONPATTRO 的轉換。與我們在第三季度分享的情況一致，新療法 AMVUTTRA 開始表格的月平均值保持在每月 60 份，這是我們在推出 AMVUTTRA 之前收到的新療法開始表格 ONPATTRO 的兩倍。

Furthermore, in the U.S., our demand generation has been healthy and balanced between community accounts and centers of excellence. And we have seen an approximately 30% increase in our prescriber base since launch, a clear signal that AMVUTTRA is expanding the opportunity for our TTR franchise. Additionally, our patient base has broadened to include a variety of newly and previously diagnosed patients starting on AMVUTTRA, with significant enthusiasm being expressed for AMVUTTRA's product profile, including quarterly subcutaneous dosing.

此外，在美國，我們的需求生成在社區賬戶和卓越中心之間保持健康和平衡。自推出以來，我們的處方藥基數增加了約 30%，這是一個明確的信號，表明 AMVUTTRA 正在擴大我們 TTR 特許經營權的機會。此外，我們的患者群已經擴大到包括各種新診斷和以前診斷的患者，他們開始使用 AMVUTTRA，對 AMVUTTRA 的產品概況表達了極大的熱情，包括每季度皮下給藥。

Meanwhile, on the access front, given our parity launch pricing, we have not faced any significant excess headwind. We've also made significant progress with formulary approvals, supporting smooth access to patients that are prescribed AMVUTTRA.

同時，在訪問方面，鑑於我們的平價啟動定價，我們沒有面臨任何重大的額外逆風。我們還在處方藥批准方面取得了重大進展，支持順利接觸開有 AMVUTTRA 處方的患者。

In our international markets, the initial launches of AMVUTTRA in Germany and Japan in Q4 experienced robust demand, with new patient starts coming from both switches from ONPATTRO as well as new-to-therapy patients that were consistent with what we experienced in the U.S. in our initial launch quarters. The new-to-therapy patients included a healthy mix of naive to therapy and switches from the competition and ONPATTRO. Our next anticipated international launch is expected in the U.K. in late Q1 2023.

在我們的國際市場上，AMVUTTRA 於第四季度在德國和日本的首次推出經歷了強勁的需求，新患者開始來自 ONPATTRO 的兩個開關以及新接受治療的患者，這與我們在美國經歷的情況一致。我們最初的發射區。新接受治療的患者包括未接受治療和從競爭和 ONPATTRO 轉換的健康組合。我們預期的下一次國際發布預計將於 2023 年第一季度末在英國舉行。

To wrap up with AMVUTTRA, we are pleased with our initial launch progress and are encouraged by the early signs that we're expanding the market opportunity for our TTR franchise.

總結 AMVUTTRA，我們對我們的初始發布進度感到滿意，並為我們正在擴大 TTR 特許經營市場機會的早期跡象感到鼓舞。

Moving to our ultrarare disease franchise. First, GIVLAARI, we achieved $47 million in global net product revenues in the fourth quarter, representing a 3% increase compared to -- compared with Q3 2022 and 16% growth versus Q4 2021. At the end of 2022, over 520 patients were on commercial GIVLAARI treatment worldwide, up from over 460 at the end of the third quarter, representing 13% quarterly patient growth. The reported 16% increase in year-over-year global net product revenue growth of GIVLAARI reflected a foreign exchange impact of 6 percentage points due to the strengthening U.S. dollar.

轉移到我們的超罕見疾病專營權。首先，GIVLAARI，我們在第四季度實現了 4700 萬美元的全球產品淨收入，與 2022 年第三季度相比增長了 3%，與 2021 年第四季度相比增長了 16%。到 2022 年底，超過 520 名患者接受了治療全球商業 GIVLAARI 治療，高於第三季度末的 460 多個，代表季度患者增長 13%。 GIVLAARI 報告的全球淨產品收入同比增長 16%，反映出由於美元走強，外匯影響增加了 6 個百分點。

In the U.S., sales of GIVLAARI were flat versus the third quarter, primarily due to the demand growth of 3%, driven by an increase in patients on therapy, which was offset by changes in inventory stocking during the quarter.

在美國， GIVLAARI 的銷售額與第三季度持平，這主要是由於接受治療的患者增加推動了 3% 的需求增長，這被本季度庫存庫存的變化所抵消。

In our international markets, GIVLAARI sales increased 10% compared with the third quarter, primarily due to the growth in patients on therapy and the timing of orders in partner markets.

在我們的國際市場， GIVLAARI 銷售額與第三季度相比增長了10%，這主要是由於接受治療的患者數量增加以及合作夥伴市場的訂單時間安排。

Moving now to our second ultrarare disease product, OXLUMO. We achieved $24 million in global net product revenues in the fourth quarter, representing a 45% increase compared with the third quarter. At the end of 2022, over 280 patients were on commercial OXLUMO treatment worldwide, up from over 230 at the end of the third quarter, representing 22% quarterly patient growth.

現在轉到我們的第二個超罕見疾病產品 OXLUMO。我們在第四季度實現了 2400 萬美元的全球淨產品收入，與第三季度相比增長了 45%。到 2022 年底，全球有超過 280 名患者接受 OXLUMO 商業治療，高於第三季度末的 230 多名，代表季度患者增長 22%。

In the U.S., sales of OXLUMO increased 38% versus the third quarter due to a growth in patients on therapy and an increase in average patient utilization during the quarter, driven by more patients on the monthly loading-dose portion of their initial treatment.

在美國，OXLUMO 的銷售額比第三季度增長了 38%，這是由於本季度接受治療的患者數量增加和平均患者利用率增加，這是由於更多患者接受了初始治療的每月負荷劑量部分。

In our international business, sales of OXLUMO increased 50% compared with the third quarter due to an increase in patients on therapy and due to the timing of orders in partner markets. Additionally, as with ONPATTRO and GIVLAARI, changes in foreign exchange rates also negatively impacted OXLUMO Q4 '22 results, with reported year-over-year growth of 24%, reflected a foreign exchange impact of 9 percentage points due to the strengthening U.S. dollar.

在我們的國際業務中，由於接受治療的患者數量增加以及合作夥伴市場的訂單時間安排，OXLUMO 的銷售額較第三季度增長了 50%。此外，與 ONPATTRO 和 GIVLAARI 一樣，外匯匯率的變化也對 OXLUMO 22 年第四季度的業績產生了負面影響，報告的同比增長為 24%，反映出由於美元走強，外匯影響增加了 9 個百分點。

In conclusion, we are pleased with the growth in revenues and patient demand achieved in Q4 and particularly with our early signs of strong performance associated with the AMVUTTRA launch, which we believe represents an important therapy option for hATTR amyloidosis patients with polyneuropathy and an accelerated growth opportunity for our TTR franchise.

總之，我們對第四季度實現的收入和患者需求的增長感到滿意，尤其是我們與 AMVUTTRA 推出相關的強勁表現的早期跡象，我們認為這代表了 hATTR 澱粉樣變性多發性神經病患者的重要治療選擇和加速增長我們的 TTR 特許經營權的機會。

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

有了這個，我現在將把它交給 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. Let me begin by updating you on our efforts in ATTR amyloidosis, where we are advancing 3 clinical-stage product candidates: patisiran; vutrisiran; and as I'll update in a moment, TTRsc04.

謝謝，Tolga，大家早上好。首先讓我向您介紹我們在 ATTR 澱粉樣變性方面的最新進展，我們正在推進 3 個臨床階段的候選產品：patisiran；維特里西蘭；我稍後會更新，TTRsc04。

First, as you've heard from Yvonne, we are delighted that our supplemental new drug application for patisiran for the cardiomyopathy of ATTR amyloidosis has been accepted by the FDA with a standard review and a PDUFA date of October 8. In their file acceptance letter, the FDA said that they have not identified any review issues. The agency also noted that they are planning to hold an Advisory Committee Meeting to discuss the application. If approved, this will allow us to extend the potential benefits of an RNAi therapeutic to the many patients with the wild-type and hereditary ATTR amyloidosis with cardiomyopathy.

首先，正如您從 Yvonne 那裡聽說的那樣，我們很高興我們針對 patisiran 治療 ATTR 澱粉樣變性心肌病的補充新藥申請已被 FDA 接受，標準審查和 PDUFA 日期為 10 月 8 日。在他們的文件接受函中， FDA 表示他們沒有發現任何審查問題。該機構還指出，他們正計劃召開諮詢委員會會議來討論該申請。如果獲得批准，這將使我們能夠將 RNAi 治療的潛在益處擴展到許多患有野生型和遺傳性 ATTR 澱粉樣變性心肌病的患者。

This filing is based on the pivotal APOLLO-B study, which demonstrated improved functional status and quality of life in patients with ATTR cardiomyopathy, given patisiran for 12 months relative to placebo. The efficacy is also supported by an encouraging safety profile and exploratory data indicating that patisiran treatment can favorably impact disease progression.

該申請基於關鍵的 APOLLO-B 研究，該研究表明，與安慰劑相比，服用帕替西蘭 12 個月後，ATTR 心肌病患者的功能狀態和生活質量有所改善。該療效還得到了令人鼓舞的安全性和探索性數據的支持，這些數據表明 patisiran 治療可以對疾病進展產生有利影響。

With the sNDA now accepted, I'd also like to share some details on our global filing plans for patisiran in ATTR amyloidosis with cardiomyopathy. We are planning to submit an sNDA in Brazil in early 2023. However, we do not plan to pursue label expansion in other regions. This is a result of the earlier-than-anticipated enrollment completion of the vutrisiran HELIOS-B study, combined with the time lines for regulatory approval and obtaining market access in these countries. As a result, we will focus our efforts in other regions to submitting an sNDA for vutrisiran, assuming positive results from the ongoing HELIOS-B study.

隨著 sNDA 現已被接受，我還想分享一些關於我們在 ATTR 澱粉樣變性心肌病中使用 patisiran 的全球申請計劃的細節。我們計劃於 2023 年初在巴西提交 sNDA。但是，我們不打算在其他地區進行標籤擴展。這是由於 vutrisiran HELIOS-B 研究的入組完成時間早於預期，加上在這些國家獲得監管批准和獲得市場准入的時間線。因此，假設正在進行的 HELIOS-B 研究取得積極成果，我們將集中精力在其他地區提交 vutrisiran 的 sNDA。

As a reminder, HELIOS-B is studying a similar population as APOLLO-B, but is designed for a primary outcomes endpoint of all-cause mortality and recurrent CV events. We remain on track to share top-line results in early 2024.

提醒一下，HELIOS-B 正在研究與 APOLLO-B 相似的人群，但它是為全因死亡率和復發性 CV 事件的主要結果終點而設計的。我們仍有望在 2024 年初分享頂級業績。

As you know, we have been evaluating a biannual dosing regimen of vutrisiran as part of the HELIOS-A randomized treatment extension or RTE, which was performed after the main portion of the study had completed. Our objective has been to see if we can provide a more convenient dosing regimen versus the already excellent profile of the 25 milligrams every 3 months regimen with maintained efficacy.

如您所知，作為 HELIOS-A 隨機治療擴展或 RTE 的一部分，我們一直在評估每半年一次的 vutrisiran 給藥方案，該方案是在研究的主要部分完成後進行的。我們的目標是看看我們是否可以提供更方便的給藥方案，而不是每 3 個月 25 毫克的方案已經非常出色並保持療效。

The primary endpoint of the RTE was non-inferiority of TTR-lowering with the 50-milligram biannual regimen versus the 25-milligram quarterly regimen as well as an acceptable safety profile. Today, we are reporting top-line results of the randomized treatment extension through month 9. As expected, non-inferiority of the 50-milligram biannual dosing regimen was indeed established, as demonstrated by mean serum TTR reduction over 9 months. However, we did note some recovery of serum TTR reduction in the 50-milligram arm towards the very end of the dosing interval at 6 months.

RTE 的主要終點是 50 毫克半年方案與 25 毫克季度方案相比在降低 TTR 方面的非劣效性以及可接受的安全性。今天，我們將報告隨機治療延長至第 9 個月的主要結果。正如預期的那樣，50 毫克半年給藥方案的非劣效性確實得到證實，9 個月的平均血清 TTR 降低證明了這一點。然而，我們確實注意到在 6 個月的給藥間隔即將結束時，50 毫克組的血清 TTR 降低有所恢復。

To illustrate this, at month 6, 80% of patients on the 25-milligram quarterly regimen achieved 80% knockdown or greater, whereas on the 50-milligram biannual regimen, 63% of patients achieved that same degree of knockdown. In other words, 37% of patients did not get to 80% TTR knockdown with the biannual regimen.

為了說明這一點，在第 6 個月時，接受 25 毫克季度方案的 80% 患者實現了 80% 或更高的抑制，而接受 50 毫克半年方案時，63% 的患者實現了相同程度的抑制。換句話說，37% 的患者在半年一次的治療方案下沒有達到 80% 的 TTR 降低率。

Vutrisiran also continues to demonstrate an acceptable safety profile. No safety signals regarding cardiac, hepatic or renal events were observed. In the RTE study, there were 6 deaths, of which 5 occurred on the 50-milligram biannual arm and [worn] occurred on the 25-milligram quarterly arm after the patient dropped out of the study. None was considered related to the study drug, and the majority occurred in patients with notable, preexisting cardiomyopathy at baseline in the context of known aggressive mutations. We are planning to present more details on these results in the Scientific Congress in early 2023.

Vutrisiran 還繼續表現出可接受的安全性。未觀察到有關心臟、肝臟或腎臟事件的安全信號。在 RTE 研究中，有 6 人死亡，其中 5 人發生在 50 毫克半年一次的手臂上，[磨損]發生在患者退出研究後的 25 毫克季度手臂上。沒有一個被認為與研究藥物有關，並且大多數發生在基線時在已知侵襲性突變的情況下患有顯著的、預先存在的心肌病的患者。我們計劃在 2023 年初的科學大會上介紹這些結果的更多細節。

Despite the support of efficacy data and safety data from the RTE, we've made the strategic decision not to move forward with regulatory submissions for the 50-milligram biannual dosing regimen of vutrisiran, as previously planned. Several factors played into that decision.

儘管 RTE 提供了療效數據和安全性數據的支持，但我們做出了戰略決定，不再按照之前的計劃推進 vutrisiran 50 毫克半年一次給藥方案的監管提交。有幾個因素影響了這個決定。

First is the dynamics of serum TTR recovery observed towards the very end of the biannual dosing interval, which we believe is suboptimal in terms of a product profile where we see clamped pharmacology in order to achieve maximal efficacy for patients.

首先是在半年一次給藥間隔即將結束時觀察到的血清 TTR 恢復動態，我們認為就產品概況而言，這是次優的，我們看到為了實現對患者的最大療效而限制了藥理學。

Second, as you heard from Tolga, the very strong initial commercial performance of AMVUTTRA in its first 2 quarters on the market, given its compelling therapeutic profile with quarterly subcutaneous dosing, along with the extremely positive feedback it has received from patients and physicians, allows us to exercise greater selectivity in advancing an innovative offering.

其次，正如您從 Tolga 那裡聽到的那樣，AMVUTTRA 在其上市的前兩個季度中非常強勁的初始商業表現，鑑於其令人信服的季度皮下給藥治療方案，以及從患者和醫生那裡收到的極其積極的反饋，允許我們在推進創新產品方面行使更大的選擇性。

And finally, we now have a new molecule targeting TTR. TTRsc04, which I am proud to announce today has entered the clinic and begun dosing in a Phase I study. ALN-TTRsc04 is an investigational RNAi therapeutic based on our IKARIA platform and offers the potential for more durable and potent TTR silencing with the possibility for annual dosing. As such, we will focus our continued innovation on advancing TTRsc04, which may offer a transformative profile. We expect top-line results from the Phase I study in late 2023.

最後，我們現在有了一種靶向 TTR 的新分子。我今天自豪地宣布 TTRsc04 已經進入臨床並開始在 I 期研究中給藥。 ALN-TTRsc04 是一種基於我們 IKARIA 平台的研究性 RNAi 治療藥物，提供了更持久和更有效的 TTR 沉默的潛力，並有可能每年給藥一次。因此，我們將把持續創新的重點放在推進 TTRsc04 上，它可能會提供變革性的概況。我們預計 I 期研究將於 2023 年底取得一線成果。

In addition to our late-stage clinical programs, we believe we have also been making great progress with our early- and mid-stage programs. A notable highlight includes zilebesiran, our investigational RNAi therapeutic for hypertension, which we believe could transform the treatment of this disease and offer a highly differentiated profile from all existing antihypertensives, including RAS inhibitors. We're thrilled to have announced that our KARDIA-1 Phase II study was fully enrolled as of December and on track to deliver top-line results in mid-2023. We also look forward to KARDIA-2 top-line results at or around year-end 2023.

除了我們的後期臨床項目外，我們相信我們的早期和中期項目也取得了很大進展。一個值得注意的亮點包括 zilebesiran，我們在研究中用於治療高血壓的 RNAi 療法，我們相信它可以改變這種疾病的治療方法，並提供與所有現有抗高血壓藥（包括 RAS 抑製劑）高度不同的特徵。我們很高興地宣布，我們的 KARDIA-1 II 期研究已於 12 月完成全部入組，並有望在 2023 年年中取得一線成果。我們也期待在 2023 年底或前後獲得 KARDIA-2 的頂級結果。

We're also working to expand delivery of RNAi therapeutics to tissues beyond the liver. To that end, we are on the cusp of seeing important data from ALN-APP, which is our first investigational RNAi therapeutic directed to the CNS and in development for the treatment of Alzheimer's disease and cerebral amyloid angiopathy. ALN-APP has the potential to offer a highly differentiated approach in Alzheimer's disease by targeting APP upstream of where antibodies currently target and has the potential to act both intracellularly and extracellularly to reduce disease-causing peptides.

我們還致力於將 RNAi 療法的遞送擴展到肝臟以外的組織。為此，我們即將看到來自 ALN-APP 的重要數據，這是我們第一個針對中樞神經系統的研究性 RNAi 療法，正在開發治療阿爾茨海默病和腦澱粉樣血管病。 ALN-APP 有潛力通過將 APP 定位在抗體當前定位的上游，並有可能在細胞內和細胞外發揮作用以減少致病肽，從而為阿爾茨海默病提供高度差異化的方法。

We believe these initial clinical data with ALN-APP, if positive, will be an important milestone, not just for this particular program, but for our overall CNS platform, to show that RNAi can achieve clinically relevant degrees of target knockdown in the CNS with a safety and dosing profile that supports further development. We remain on track to report top-line results from the Phase I study in early 2023.

我們相信，這些 ALN-APP 的初步臨床數據，如果呈陽性，將是一個重要的里程碑，不僅對於這個特定項目，而且對於我們的整個 CNS 平台，以表明 RNAi 可以在 CNS 中實現臨床相關的目標敲低程度支持進一步開發的安全和劑量配置文件。我們仍有望在 2023 年初報告 I 期研究的主要結果。

These are just a few highlights from our broad and innovative pipeline, driven by our underlying organic product engine that we expect will deliver sustainable innovation and represents a key growth driver for Alnylam in the years to come.

這些只是我們廣泛而創新的產品線中的幾個亮點，這些產品線由我們潛在的有機產品引擎驅動，我們預計該引擎將帶來可持續的創新，並成為 Alnylam 未來幾年的主要增長動力。

To wrap up these highlights, we're excited to have submitted a CTA filing for ALN-KHK in type 2 diabetes, with a Phase I start expected imminently. In addition, our partners at Regeneron have begun dosing in a Phase I trial of ALN-PNP in NASH.

為了總結這些亮點，我們很高興提交了 ALN-KHK 治療 2 型糖尿病的 CTA 申請，預計第一階段即將開始。此外，我們在 Regeneron 的合作夥伴已經開始在 NASH 中進行 ALN-PNP 的 I 期試驗。

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

有了這個，現在讓我把它交給傑夫來審查我們的財務業績和即將到來的里程碑。傑夫？

Thanks, Pushkal, and good morning, everyone. I'm pleased to be presenting Alnylam's Q4 and full year 2022 financial results, which underscore Alnylam's strong commercial capabilities and operational excellence. After commenting on our fourth quarter and full year results, I will also provide our financial guidance for 2023.

謝謝，Pushkal，大家早上好。我很高興介紹 Alnylam 的第四季度和 2022 年全年財務業績，這凸顯了 Alnylam 強大的商業能力和卓越的運營能力。在評論我們的第四季度和全年業績後，我還將提供我們 2023 年的財務指導。

Turning now to a summary of our full P&L results for the fourth quarter and full year. Total product revenues for 2022 were $894 million or 35% growth versus 2021 or 43% on a constant exchange rate basis with growth contributions from all 4 commercial products. Net revenue from collaborations for the fourth quarter was approximately $71 million, representing an 18% increase compared with Q4 2021, primarily due to increased revenue from our collaboration with Regeneron from increased manufacturing activities in the quarter. For the full year, net revenue from collaborations was $135 million, representing a 25% decrease compared with 2021, primarily due to a decrease in revenue recognized in connection with our collaboration agreements to Regeneron and Vir contributed to reduced research and manufacturing activities and timing of reimbursable activities.

現在轉向我們第四季度和全年的完整損益結果摘要。 2022 年的產品總收入為 8.94 億美元，與 2021 年相比增長 35%，按固定匯率計算增長 43%，所有 4 種商業產品的增長都做出了貢獻。第四季度合作淨收入約為 7100 萬美元，與 2021 年第四季度相比增長 18%，這主要是由於本季度製造活動增加，我們與再生元合作的收入增加。全年，合作淨收入為 1.35 億美元，與 2021 年相比下降 25%，這主要是由於我們與 Regeneron 和 Vir 的合作協議確認的收入減少導致研究和製造活動減少以及時間安排有償活動。

Our non-GAAP R&D expenses increased 16% in the fourth quarter of 2022 compared to the same period in the prior year, primarily due to increases in headcount to support our R&D pipeline and development expenses associated with the KARDIA-1 and KARDIA-2 zilebesiran Phase II studies. Our non-GAAP SG&A expenses increased 15% in the fourth quarter of 2022 compared to the same period in the prior year, primarily due to increased headcount and other investments in support of the global launch of AMVUTTRA and other corporate expenses to support the scaling of our business.

我們的非美國通用會計準則研發費用在 2022 年第四季度與去年同期相比增長了 16%，這主要是由於支持我們的研發管道的人數增加以及與 KARDIA-1 和 KARDIA-2 zilebesiran 相關的開發費用II 期研究。我們的非 GAAP SG&A 費用在 2022 年第四季度與去年同期相比增長了 15%，這主要是由於增加了員工人數和其他投資以支持 AMVUTTRA 的全球推出以及其他公司費用以支持擴展我們的業務。

Our combined non-GAAP R&D and SG&A expenses were approximately $1.4 billion for the full year 2022, representing 14% growth versus 2021, as we continue to advance our pipeline and deliver strong top-line growth while maintaining discipline in how we invest in our operations.

2022 年全年，我們的非 GAAP 研發和 SG&A 支出合計約為 14 億美元，比 2021 年增長 14%，因為我們繼續推進我們的管道並實現強勁的收入增長，同時保持我們對運營投資方式的紀律.

Our non-GAAP operating loss for 2022 was $554 million or approximately flat versus 2021. We do anticipate reducing our non-GAAP operating loss in 2023, as you will hear when I provide our 2023 financial guidance, as we remain focused on achieving a self-sustainable financial profile by 2025, aligned with our P5x25 goals.

我們 2022 年的非 GAAP 營業虧損為 5.54 億美元，與 2021 年基本持平。我們確實預計 2023 年會減少我們的非 GAAP 營業虧損，正如您在我提供 2023 年財務指導時會聽到的那樣，因為我們仍然專注於實現自我- 到 2025 年實現可持續的財務狀況，與我們的 P5x25 目標保持一致。

Finally, we ended the year with cash, cash equivalents and marketable securities of $2.2 billion compared to $2.4 billion at the end of 2021, with the decrease primarily due to our operating loss in 2022, which was partially offset by approximately $265 million received from Employee Option Award exercises and approximately $135 million from our convertible debt financing. We continue to believe that our current cash balance will bridge us to financial self-sustainability, an enviable position in today's market environment.

最後，我們在年底的現金、現金等價物和有價證券為 22 億美元，而 2021 年底為 24 億美元，減少的主要原因是我們在 2022 年的經營虧損，部分被從員工那裡收到的約 2.65 億美元所抵消期權獎勵行使和來自我們的可轉換債務融資的約 1.35 億美元。我們仍然相信，我們目前的現金餘額將使我們能夠實現財務自給自足，這在當今的市場環境中是一個令人羨慕的地位。

Now turning to our financial guidance for 2023. Starting with net product revenues, we are providing combined net product revenue guidance for ONPATTRO, GIVLAARI, OXLUMO and AMVUTTRA. Our guidance assumes the sNDA for patisiran for ATTR amyloidosis with cardiomyopathy in the U.S. will be approved by the PDUFA date on October 8, 2023, and also assumes foreign exchange rates as of December 31, 2022. We anticipate combined net product revenues for these 4 products will be between $1.2 billion and $1.285 billion, with the projected reported growth range versus 2022 of 34% to 44%.

現在轉向我們 2023 年的財務指導。從產品淨收入開始，我們為 ONPATTRO、GIVLAARI、OXLUMO 和 AMVUTTRA 提供綜合產品淨收入指導。我們的指南假設 patisiran 用於治療 ATTR 澱粉樣變性心肌病的 sNDA 在美國將在 2023 年 10 月 8 日的 PDUFA 日期之前獲得批准，並且還假設截至 2022 年 12 月 31 日的匯率。我們預計這 4 個產品的合併淨產品收入產品將在 12 億美元至 12.85 億美元之間，與 2022 年相比，預計增長范圍為 34% 至 44%。

As you can see, we are also providing constant exchange rate growth guidance for our net product revenues this year with a projected range of 34% to 44%, highlighting no current difference between our reported and constant exchange rate growth guidance.

如您所見，我們還為今年的產品淨收入提供了恆定匯率增長指導，預計範圍為 34% 至 44%，強調我們報告的匯率增長指導與恆定匯率增長指導之間目前沒有差異。

Our guidance for net revenue from collaborations and royalties is a range between $100 million and $175 million, with the midpoint of the range approximately flat versus 2022. We anticipate the collaboration revenue associated with our partnership with Regeneron and LEQVIO royalties from Novartis will drive the majority of our collaboration and royalty revenue in 2023.

我們對合作和特許權使用費淨收入的指導在 1 億美元至 1.75 億美元之間，該範圍的中點與 2022 年大致持平。我們預計與再生元合作的合作收入和來自諾華的 LEQVIO 特許權使用費將推動大部分我們在 2023 年的合作和特許權使用費收入。

Our guidance for combined non-GAAP R&D and SG&A expenses is a range between $1.575 billion and $1.65 billion. The midpoint of the guidance range represents a projected 13% increase compared with 2022. Growth highlights for R&D expense in 2023 include increased investment in zilebesiran as we progress the KARDIA-1 and KARDIA-2 Phase II studies, initial investment in TTRsc04 as well as growth in pre-DC and IND-enabling efforts across our preclinical portfolio as we continue to invest in creating new organic growth opportunities for the future.

我們對合併的非 GAAP 研發和 SG&A 費用的指導在 15.75 億美元至 16.5 億美元之間。指導範圍的中點代表預計與 2022 年相比增長 13%。2023 年研發費用的增長亮點包括隨著我們推進 KARDIA-1 和 KARDIA-2 II 期研究而增加對 zilebesiran 的投資、對 TTRsc04 的初始投資以及隨著我們繼續投資於為未來創造新的有機增長機會，我們臨床前產品組合中 DC 前和 IND 支持工作的增長。

Growth highlights for SG&A expense in 2023 include increased medical and commercial investment as we prepare for the potential launch of patisiran in the U.S. for ATTR amyloidosis with cardiomyopathy.

2023 年 SG&A 費用的增長亮點包括增加醫療和商業投資，因為我們準備在美國可能推出 patisiran 治療 ATTR 澱粉樣變性心肌病。

Let me now turn from financials and discuss some key goals and upcoming milestones slated for early 2023. We will, of course, be executing on the global commercialization of our products: ONPATTRO, AMVUTTRA, GIVLAARI and OXLUMO. We expect to complete enrollment in the KARDIA-2 Phase II study of zilebesiran. Top-line results from our Phase I study of ALN-APP in patients with early-onset Alzheimer's disease is on track for early 2023. With our partner programs, Vir expects additional results from Phase II combination trials of ALN-HBV02, and Regeneron plans to initiate a Phase II study of ALN-HSD in patients with NASH.

現在讓我從財務上談談一些關鍵目標和定於 2023 年初即將到來的里程碑。當然，我們將執行我們產品的全球商業化：ONPATTRO、AMVUTTRA、GIVLAARI 和 OXLUMO。我們預計將完成 Zilebesiran 的 KARDIA-2 II 期研究的註冊。我們對早發性阿爾茨海默氏病患者進行的 ALN-APP I 期研究的一線結果有望在 2023 年初取得。通過我們的合作夥伴計劃，Vir 預計 ALN-HBV02 和 Regeneron 計劃的 II 期聯合試驗將獲得更多結果在 NASH 患者中啟動 ALN-HSD 的 II 期研究。

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

現在讓我把它轉回克里斯汀並協調我們的問答環節。克里斯汀？

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

謝謝你，傑夫。接線員，我們現在將打開您的問題的電話。對於那些提交的人，我們想請您限制自己每個問題一個問題，如果您有其他問題，請回到隊列中。

(Operator Instructions)

（操作員說明）

Our first question comes from the line of Ritu Baral from Cowen.

我們的第一個問題來自 Cowen 的 Ritu Baral。

Yvonne, I wanted to ask about just the potential topics of the Advisory Committee meeting. What do you think at this point, what is Alnylam planning on addressing during the Advisory Committee meeting, if no review -- I'm sorry, no review issues have yet been identified in the communication? Are there points during the sNDA review that, by law, interaction is required between the sponsor and the regulator to help you set that out?

伊馮娜，我想問的只是諮詢委員會會議的潛在主題。您目前怎麼看，Alnylam 計劃在諮詢委員會會議期間解決什麼問題？在 sNDA 審查期間，是否有幾點表明，根據法律，申辦方和監管機構之間需要互動以幫助您確定這一點？

Ritu, thank you very much for that question. I mean, as you know, we were very pleased with the results from the APOLLO-B study and pleased that the FDA accepts in our application. And as you point out, did not identify any review issues to date. Whether you have an adcom or not is entirely up to the FDA. We have no indication at this point in time with respect to any specific areas to address as any potential advisory committee. But we look forward to engaging with the FDA through this process and the sharing our data. Beyond that, there's not a lot else we can say at this point in time.

Ritu，非常感謝你提出這個問題。我的意思是，如您所知，我們對 APOLLO-B 研究的結果非常滿意，並且很高興 FDA 接受我們的申請。正如您所指出的，迄今為止沒有發現任何審核問題。您是否擁有 adcom 完全取決於 FDA。目前，我們沒有任何跡象表明任何特定領域需要作為任何潛在的諮詢委員會處理。但我們期待通過這個過程與 FDA 合作並共享我們的數據。除此之外，目前我們無話可說。

So no legal interactions required for the sNDA process in the near future with you guys?

那麼在不久的將來，sNDA 流程不需要與你們進行法律互動嗎？

Well, we will get information as the -- more details around the advisory committee at the point in time. But at this stage, we have no further information that we can provide. I mean the only update that we are required to provide the FDA is the 120-day safety update.

好吧，我們將及時獲得有關諮詢委員會的更多詳細信息。但在現階段，我們無法提供更多信息。我的意思是我們需要向 FDA 提供的唯一更新是 120 天安全更新。

And your next question comes from the line of David Lebowitz from Citi.

你的下一個問題來自花旗銀行的 David Lebowitz。

With respect to the 6-month dosing of AMVUTTRA falling short and being discontinued, what learnings are you taking from that to the carrier program? And is it changing your strategy with respect to how you're looking at that particular therapy? And then just a little tag on, do you think that the lack of the biannual dose substantially changes anything for the AMVUTTRA's past prospects?

關於 AMVUTTRA 的 6 個月劑量不足和停藥，您從中學到了什麼知識用於承運人計劃？它是否改變了您看待特定療法的策略？然後只是一點點，你認為缺乏一年兩次的劑量是否會大大改變 AMVUTTRA 過去的前景？

Right. So I'll start off and then invite Pushkal to contribute. I think really the first thing to say is that the quarterly regimen of AMVUTTRA has really been a game changer for patients with TTR polyneuropathy, and we're really pleased with the profile. You heard from Tolga earlier how well the launch is going. So really, the decision to not move forward with a 6-month regimen was a strategic one. We want to be able to focus on the quarterly AMVUTTRA regimen in the near term. And then as you've heard, and you touched on this, progress TTRsc04 based on our IKARIA platform, where we believe that's a real potential for knockdown, TTR knockdown upgrades to 90% and potentially annual dosing as well, which we think is then a real step-forward for patients. I mean, Pushkal, any commentary on the learnings? I suppose what we've learned is more about the profile of the 6 months new regimen. Anything else to add?

正確的。所以我會開始，然後邀請 Pushkal 參與。我認為首先要說的是 AMVUTTRA 的季度方案確實改變了 TTR 多發性神經病患者的遊戲規則，我們對這種情況感到非常滿意。你之前從 Tolga 那裡聽說了發布的進展情況。所以說真的，不推進 6 個月療程的決定是一個戰略性的決定。我們希望能夠在短期內專注於季度 AMVUTTRA 養生法。然後正如您所聽到的，並且您談到了基於我們的 IKARIA 平台的 TTRsc04 進展，我們認為這是擊倒的真正潛力，TTR 擊倒升級到 90% 以及潛在的年度劑量，我們認為這是然後對患者來說是一個真正的進步。我的意思是，Pushkal，對學習的任何評論？我想我們學到的更多是關於 6 個月新方案的概況。還有什麼要補充的嗎？

Yes. No, I think the only thing that I would add to what you said, Yvonne, is I mean, a, it's reaffirmed the potency and the power of the 25-milligram quarterly regimen, where we saw excellent clamped pharmacology with the quarterly dosing, that reaffirms the profile that we saw in the original HELIOS-A study. And I think, Dave, to your other point, I think -- and as Yvonne highlighted, we're really excited that sc04 is now in the clinic, and we will get data shortly later this year around what that's looking like in the Phase I study.

是的。不，我想我唯一要補充的是你所說的，伊馮，我的意思是，它重申了每季度 25 毫克方案的效力和力量，我們看到每季度一次給藥具有出色的箝制藥理學，這重申了我們在最初的 HELIOS-A 研究中看到的概況。我想，Dave，關於你的另一個觀點，我想——正如 Yvonne 強調的那樣，我們真的很高興 sc04 現在進入臨床，我們將在今年晚些時候獲得有關 Phase 的數據我學習。

And we're optimistic, based on the preclinical data and the power of the IKARIA platform, that we will see more potent and more durable knockdown and enabling a possible annual dosing regimen with that. So I think we're really in a fortunate position that our research engine has been able to bring forward this sc04 molecule that we can bring into the clinic. It allows us to progress innovation to these patients.

我們很樂觀，基於臨床前數據和 IKARIA 平台的力量，我們將看到更有效和更持久的擊倒，並以此實現可能的年度給藥方案。所以我認為我們真的很幸運，我們的研究引擎已經能夠提出我們可以帶入臨床的這種 sc04 分子。它使我們能夠為這些患者推進創新。

Your next question comes from the line of Tazeen Ahmad from Bank of America.

你的下一個問題來自美國銀行的 Tazeen Ahmad。

Mine is on APP for the expected top line that's due in the beginning of this year. Can you just give us some color on what data exactly you're planning on presenting? And how we should interpret that data, what would be clinically meaningful? And do you also plan on presenting any flat clearance data with that top line?

我的應用程序在今年年初到期的預期頂線。你能給我們一些關於你計劃呈現哪些數據的顏色嗎？我們應該如何解讀這些數據，哪些數據具有臨床意義？您是否還計劃在該頂線顯示任何平面清關數據？

We don't actually kind of hear all of the questions. Do you mind perhaps repeating it and maybe focusing on just one question?

我們實際上並沒有聽到所有的問題。您是否介意重複它並只關註一個問題？

Yes. The question is on what you're going to present at the top line? What should we include in that assumption of what you're going to be presenting? So would you be presenting (inaudible) with that?

是的。問題是你要在頂行展示什麼？我們應該在您將要展示的內容的假設中包括什麼？那麼你會用那個來展示（聽不清）嗎？

That's really clear, so top-line data from the ALN-APP study. Pushkal?

這真的很清楚，所以來自 ALN-APP 研究的頂級數據。普什卡爾？

Yes. Thanks, Tazeen. So we're really excited about the ALN-APP program. It's our first foray into the CNS. We're still on track to have top-line data in the first half of this year. As a reminder, this is a study in patients with early-onset Alzheimer's disease. We're in the single-ascending dose phase of that study. And what we are hoping to report out on will be safety and tolerability, which is the primary endpoint. This is the first time we're giving intrathecal injection with the C16 conjugate and then looking for target engagement and knockdown of soluble APP alpha and beta. So we have very good pharmacodynamic markers that can point to target engagement. And we'll want to see evidence of target engagement there that we're seeing good pharmacology in the brain. So those are really the key things that we'll be reporting on later this -- in the first half of the year.

是的。謝謝，塔贊。所以我們對 ALN-APP 計劃感到非常興奮。這是我們首次涉足中樞神經系統。我們仍有望在今年上半年獲得一線數據。提醒一下，這是一項針對早發性阿爾茨海默病患者的研究。我們正處於該研究的單劑量遞增階段。我們希望報告的是安全性和耐受性，這是主要終點。這是我們第一次使用 C16 偶聯物進行鞘內註射，然後尋找可溶性 APP alpha 和 beta 的目標參與和敲低。所以我們有非常好的藥效學標記可以指向目標參與。我們希望看到目標參與的證據，我們在大腦中看到了良好的藥理學。因此，這些確實是我們將在今年上半年報告的關鍵內容。

And your next question comes from the line of Salveen Richter from Goldman Sachs.

你的下一個問題來自高盛的 Salveen Richter。

This is Tommie on for Salveen. For HELIOS-B, can you remind us some of the rationale behind using all-cause mortality instead of cardiovascular mortality in the composite primary endpoint? And is there one that's preferred by physicians and regulators?

這是 Salveen 的 Tommie。對於 HELIOS-B，您能否提醒我們在復合主要終點中使用全因死亡率而不是心血管死亡率背後的一些基本原理？是否有醫生和監管機構偏愛的產品？

Thanks, Salveen. And I guess that's a question straight for you, Pushkal.

謝謝，薩爾文。 Pushkal，我想這是一個直接問你的問題。

Yes. So Salveen, I think when we look at -- when we designed the HELIOS-B study, we really want to ultimately show the benefit of the drug on the totality of the experience of patients with this disease. And all-cause mortality and recurrent CV event endpoint really captures -- maximizes the number of events that we can capture in the course of the study, which aids in the powering of the study and also becomes a very clinically meaningful effect.

是的。所以 Salveen，我認為當我們看 - 當我們設計 HELIOS-B 研究時，我們真的想最終展示藥物對這種疾病患者的整體體驗的好處。全因死亡率和復發性 CV 事件終點真正捕獲——最大化我們在研究過程中可以捕獲的事件數量，這有助於研究的動力，也成為一個非常具有臨床意義的效果。

Certainly, there can be analyses that are looked at under that as secondaries or post hoc that look at the various types of mortality events, but that's the basic explanation.

當然，可以將分析視為次要或事後分析，以查看各種類型的死亡事件，但這是基本解釋。

The next question comes from the line of Maury Raycroft from Jefferies.

下一個問題來自 Jefferies 的 Maury Raycroft。

I was wondering if you have a tentative date scheduled for the adcom? And you've mentioned adding the 120-day safety data from APOLLO-B open-label extension. But I'm wondering if you can discuss possible scenarios where you may be able to supplement the sNDA with additional efficacy or safety data from APOLLO-B open-label extension and/or the HELIOS-B study.

我想知道您是否為 adcom 安排了暫定日期？你提到從 APOLLO-B 開放標籤擴展中添加 120 天的安全數據。但我想知道您是否可以討論可能的情況，在這些情況下，您可以使用來自 APOLLO-B 開放標籤擴展和/或 HELIOS-B 研究的額外療效或安全性數據來補充 sNDA。

Yes. So Maury, maybe a couple of questions in there. We don't have a formal date yet. That's something -- again, we've released what we understand at the moment from the agency's correspondence with us. So we'll look forward to getting additional information on that.

是的。那麼 Maury，也許有幾個問題。我們還沒有正式約會。那是什麼——再次，我們已經發布了我們目前從該機構與我們的通信中了解到的內容。因此，我們期待獲得更多相關信息。

As the -- in terms of the 18-month data, look, we're in the process of getting and reviewing the APOLLO-B open-label extension data. As a reminder, everybody crosses over to active drug at month 12. And we'll certainly share those data at an appropriate scientific meeting. And with regard to the agency, we'll be supplying whatever they need to facilitate their review. And so we're looking forward to sharing things -- the data with them, both from the main study and as they need from the open-label extension. The day-120 safety update is primarily focused on safety update data. So that will also be a parallel process.

作為——就 18 個月的數據而言，看，我們正在獲取和審查 APOLLO-B 開放標籤擴展數據。提醒一下，每個人都在第 12 個月開始使用活性藥物。我們當然會在適當的科學會議上分享這些數據。對於該機構，我們將提供他們需要的任何東西來促進他們的審查。因此，我們期待與他們分享一些東西——來自主要研究的數據以及他們需要的來自開放標籤擴展的數據。第 120 天安全更新主要集中在安全更新數據上。所以這也將是一個並行過程。

Your next question comes from the line of Paul Matteis with Stifel.

您的下一個問題來自 Paul Matteis 與 Stifel 的合作。

Congrats on the progress. I was -- I thought it was really interesting that you included potential sales from ONPATTRO in TTR cardiomyopathy in guidance, given that it's under review, given that there is an adcom. And I guess, is it the right interpretation of that decision that the company continues to have very high conviction that the APOLLO-B data should lead to an approval, and that was enough for you to plan financially and guide around that?

祝賀進步。我是——我認為你將 ONPATTRO 的潛在銷售包括在 TTR 心肌病的指導中真的很有趣，因為它正在審查中，因為有一個 adcom。我想，公司繼續堅信 APOLLO-B 數據應該獲得批准，這是否足以讓您進行財務規劃並圍繞此進行指導？

Well, I mean, I'll start and then hand it over to Jeff in terms of how we thought about planning. I mean clearly, we do believe that the APOLLO-B study has delivered actually very impactful results, both in terms of health status and disease. We've talked about the efficacy end points in some detail. And clearly, we are planning for the Advisory Committee as notified by the FDA. And obviously, we will have to await the FDA's determination on our submission. But we believe that we have an efficacy and safety package here that is pretty compelling. Jeff, do you want to speak a little bit to how we thought about the ONPATTRO CM revenues?

好吧，我的意思是，我將開始，然後就我們如何考慮規劃將其交給 Jeff。我的意思很明確，我們確實相信 APOLLO-B 研究實際上在健康狀況和疾病方面都取得了非常有影響力的結果。我們已經詳細討論了療效終點。很明顯，我們正在按照 FDA 的通知為諮詢委員會制定計劃。顯然，我們將不得不等待 FDA 對我們提交的材料做出決定。但我們相信我們這裡有一個非常引人注目的功效和安全包。 Jeff，你想談談我們對 ONPATTRO CM 收入的看法嗎？

Yes. I mean, Paul, you're right. I mean, we flagged that in the guidance on the slide that we assume that. Again, given the timing of that, given that it's in the fourth quarter, the impact of that from a revenue perspective this year is going to be relatively modest. And so not -- that doesn't really have a significant impact on the financial guidance we've given for the year as a result. If approved, we would expect more significant impact next year.

是的。我的意思是，保羅，你是對的。我的意思是，我們在我們假定的幻燈片指南中標記了這一點。同樣，考慮到時間，考慮到它是在第四季度，從今年的收入角度來看，它的影響將相對溫和。因此，這並沒有真正對我們今年給出的財務指導產生重大影響。如果獲得批准，我們預計明年會產生更大的影響。

The next question comes from the line of Gena Wang with Barclays.

下一個問題來自 Gena Wang 與 Barclays 的對話。

I have one question regarding the APP program. What would be the ideal clinical profile regarding percentage of knockdown and the frequency of dosing? Any negative reason from vutrisiran biannual dosing data regarding frequency of dosing for the APP program?

我有一個關於APP程序的問題。關於擊倒百分比和給藥頻率的理想臨床概況是什麼？ vutrisiran 一年兩次的給藥數據對 APP 程序的給藥頻率有任何負面影響嗎？

Yes, Gena, thanks for your question. So I guess a couple of things in there. What's the ideal profile? So look, I think this is -- we've said before that we don't have the -- from genetic data, we would imagine that we would want to get to close to about 50% knockdown of ALN-APP of amyloid precursor protein. We think that's probably around the target range to get to a therapeutic effect. But at the end of the day, no one really knows. And so that's kind of where we're shooting for. But this is, again, an initial single-ascending dose study. We'll be providing some interim data. And so we'll be working our way up to get to higher levels of knockdown as the data allow, and so that's point one.

是的，吉娜，謝謝你的問題。所以我猜裡面有幾件事。什麼是理想的個人資料？所以看，我認為這是——我們之前說過，我們沒有——來自遺傳數據，我們可以想像我們希望將澱粉樣蛋白前體的 ALN-APP 擊倒接近 50%蛋白質。我們認為這可能在達到治療效果的目標範圍內。但歸根結底，沒有人真正知道。這就是我們的目標。但這又是一項初始的單劑量遞增研究。我們將提供一些臨時數據。因此，我們將努力在數據允許的情況下達到更高水平的擊倒，這就是第一點。

In terms of the frequency of dosing, look, the preclinical data that we have suggests that this may be a relatively infrequently-dosed molecule. We've seen knockdown lasting over 6 months in the nonhuman primate studies that we've done with ALN-APP. So we're very encouraged with the potential that this could be a quarterly or potentially biannual-dosed drug in the CNS. But again, the data will inform that.

就給藥頻率而言，看，我們擁有的臨床前數據表明這可能是一種相對不頻繁給藥的分子。在我們使用 ALN-APP 進行的非人類靈長類動物研究中，我們已經看到持續 6 個月以上的擊倒。因此，我們對這可能成為中樞神經系統中每季度或可能每半年給藥一次的藥物的潛力感到非常鼓舞。但同樣，數據會說明這一點。

I don't think there's any particular read-through from the vutrisiran-randomized treatment extension. That's a different molecule and it's given to a different space. It's a different conjugate. And as you know, we continued to -- our scientists continue to hone our chemistry all the time, but a lot of that is also molecule and target-dependent. So we're very encouraged by the data we've had so far, non-clinically and really looking forward to the clinical data emerging shortly.

我認為 vutrisiran 隨機治療擴展沒有任何特別的通讀。那是一個不同的分子，它被賦予了不同的空間。這是一個不同的共軛。正如你所知，我們繼續 - 我們的科學家一直在繼續磨練我們的化學反應，但其中很多也取決於分子和目標。因此，我們對迄今為止的非臨床數據感到非常鼓舞，並且非常期待很快出現的臨床數據。

Your next question comes from the line of Luca Issi with RBC Capital.

你的下一個問題來自 RBC Capital 的 Luca Issi。

Congrats on the progress. I have a quick one on HELIOS-B. I think there's a few docs out there that are convinced that actually the drug is making an impact for their patients with cardiomyopathy, but they are just worried that this trial is not long enough to actually show a convincing separation of the curves. Is there a scenario where you can amend the protocol, so you don't read out the primary endpoint with the last patients who reached the 30-months mark, but rather after a prespecified number of events? Any thoughts there, much appreciated.

祝賀進步。我在 HELIOS-B 上有一個快速的。我認為有一些醫生確信該藥物實際上對他們的心肌病患者產生了影響，但他們只是擔心該試驗的時間不夠長，無法真正顯示出令人信服的曲線分離。是否存在您可以修改方案的情況，這樣您就不會讀出最後一位達到 30 個月大關的患者的主要終點，而是在預先指定的事件數量之後讀出？那裡有任何想法，非常感謝。

Yes. Luca, I think there's -- first of all, it's great that you're getting that sort of feedback. We're obviously encouraged overall by the profile of vutrisiran that we're seeing from patients out there.

是的。盧卡，我認為——首先，你能得到這樣的反饋真是太好了。我們從那裡的患者那裡看到的 vutrisiran 的概況顯然使我們總體上感到鼓舞。

In terms of the study design, I think we've -- a, I'd just remind you, we have a track record of working in this space for quite a while in executing successful studies. Our teams have gone through, and we feel very good about the design of the study and the execution of the study.

在研究設計方面，我認為我們已經 - a，我只是提醒你，我們在這個領域有很長一段時間在執行成功研究方面的工作記錄。我們的團隊已經通過了，我們對研究的設計和研究的執行感覺非常好。

As a reminder, we've got variable follow-up for 30 to 36 months. And this study builds upon the success in what we've seen in terms of encouraging data coming out of APOLLO-B, where we saw positive impacts on functional endpoints, quality of life, evidence of potential delays in disease progression and favorable impacts on echocardiographic parameters, technicians. There's a lot of positive data there, and HELIOS-B is twice as large and about 3x as long. So we feel good about the design and execution of that study, and we're not planning, at this point, to make any changes.

提醒一下，我們有 30 到 36 個月的可變隨訪。這項研究建立在我們所看到的令人鼓舞的 APOLLO-B 數據成功的基礎上，我們看到了對功能終點、生活質量的積極影響、疾病進展潛在延遲的證據以及對超聲心動圖的有利影響參數, 技術人員.那裡有很多積極的數據，HELIOS-B 是它的兩倍大，大約是它的三倍長。因此，我們對該研究的設計和執行感到滿意，目前我們不打算進行任何更改。

Yes. Spot on (inaudible). I mean, right now, we're focused on robust execution and bringing this home and sharing results with you in early 2024.

是的。現場（聽不清）。我的意思是，現在，我們專注於穩健的執行，並在 2024 年初將其帶回家並與您分享結果。

And your next question comes from the line of Jessica Fye with JPMorgan.

你的下一個問題來自 JPMorgan 的 Jessica Fye。

This is [Jill] for Jess. So 2 questions from us on the sNDA of ONPATTRO. In the case that the FDA will request any new data or in the case that you might want to send more data to the FDA, do you expect any type of PDUFA extension because of the new data submission? And then secondly, we know that the cardiovascular outcome data from BridgeBio Tribute CM trial will be available in July. So just curious, would you be watching for the data from the Tribute CM? And if any thoughts you can share with us regarding the kind of potential impact on the Tribute data on your thinking of the change in patient population and anything along those lines.

這是 Jess 的 [Jill]。所以我們有 2 個關於 ONPATTRO 的 sNDA 的問題。如果 FDA 將要求任何新數據，或者如果您可能想向 FDA 發送更多數據，您是否期望由於新數據提交而進行任何類型的 PDUFA 擴展？其次，我們知道 BridgeBio Tribute CM 試驗的心血管結果數據將於 7 月提供。很好奇，您會關注 Tribute CM 的數據嗎？如果您有任何想法可以與我們分享，關於對 Tribute 數據的潛在影響，您對患者人數變化的想法以及這些方面的任何事情。

Two questions for you, really here, Pushkal. One on the sNDA with ONPATTRO and requirement for new data and potential extensions to the date. And then I think some questions around our perspectives on BridgeBio polyneuropathy outcome study.

有兩個問題，真的在這裡，Pushkal。一個在 sNDA 上與 ONPATTRO 和對新數據的要求以及對日期的潛在擴展。然後我想一些關於我們對 BridgeBio 多發性神經病結果研究的觀點的問題。

Yes. Thank you. Look, in terms of the impact, if we're asked to supply additional data, I really can't speculate. Certainly, we will provide whatever data the agency requires to facilitate their review. And we look forward to sharing that data in the course of questions that come from the agency and at the Advisory Committee. The FDA has declared a PDUFA date of October 8, and I know they'll be striving to achieve that, and we'll update if there's any changes to that based on their requests.

是的。謝謝。看，就影響而言，如果我們被要求提供額外的數據，我真的無法推測。當然，我們將提供該機構需要的任何數據以促進他們的審查。我們期待在該機構和諮詢委員會提出問題的過程中分享這些數據。 FDA 已宣布 PDUFA 日期為 10 月 8 日，我知道他們會努力實現這一目標，如果根據他們的要求對此有任何更改，我們會進行更新。

In terms of the [acarametas] data, look, we look forward to seeing the results. I think it's scheduled for the middle of the year. But I don't think that really changes anything for us in the context of the APOLLO-B sNDA. That study is completed and under review, and so we'll certainly be looking for those results and watching them, but there's -- I don't see any really particular impact on the APOLLO-B sNDA.

就 [acarametas] 數據而言，看，我們期待看到結果。我認為它定於今年年中。但我認為，在 APOLLO-B sNDA 的背景下，這不會真正改變我們的任何事情。該研究已經完成並正在審查中，因此我們當然會尋找這些結果並觀察它們，但是 - 我沒有看到對 APOLLO-B sNDA 有任何真正特別的影響。

Yes. So informative for the field.

是的。為該領域提供了豐富的信息。

Yes.

是的。

But have no real kind of consequence of specific programs.

但是沒有具體程序的真正後果。

Correct. Yes.

正確的。是的。

And your next question comes from the line of Mike Ulz with Morgan Stanley.

你的下一個問題來自 Mike Ulz 與 Morgan Stanley 的對話。

Maybe just a quick one on AMVUTTRA and polyneuropathy. I noticed you got a J code in early January. Just curious what impact you think that could have on the trajectory of the launch? And is it potential we could see an inflection there?

也許只是關於 AMVUTTRA 和多發性神經病的快速介紹。我注意到您在 1 月初收到了 J 代碼。只是好奇您認為這會對發射軌跡產生什麼影響？我們是否有可能在那裡看到拐點？

That's a nice short question for Tolga, implications of the -- our receipt for the J code.

對於 Tolga 來說，這是一個很好的簡短問題——我們收到 J 代碼的含義。

Right. Mike, thanks for the question. We're very pleased with the fact that the J code -- we received the J code as a -- on the due date. Prior to the J code, we already had a generic J code that allowed us to be able to have access to provide the right access to our patients in the U.S. Therefore, we wouldn't necessarily be expecting any significant change.

正確的。邁克，謝謝你的提問。我們很高興 J 代碼——我們在到期日收到了 J 代碼。在 J 代碼之前，我們已經有了一個通用的 J 代碼，它使我們能夠為美國的患者提供正確的訪問權限。因此，我們不一定期望有任何重大變化。

Now in terms of the uptake, it already itself has been -- as Yvonne put it, there has been a game changer. We have doubled the number of start forms that we would normally receive in a steady state of ONPATTRO. Therefore, we're very pleased with the accelerated growth that are parity pricing at launch as well as our good value-based access strategies that we were able to establish prior to the launch. That's really allowing us to have a smooth sailing in terms of the access front. And the growth is really coming from -- thanks to the profile of the product as well as our efforts in expanding the prescriber base for the polyneuropathy across the U.S. as well as now, in Japan and Germany.

現在就接受度而言，它本身已經——正如 Yvonne 所說，已經改變了遊戲規則。我們已經將通常在 ONPATTRO 穩定狀態下收到的開始表格數量增加了一倍。因此，我們對啟動時的平價定價以及我們能夠在啟動前建立的良好的基於價值的訪問策略的加速增長感到非常滿意。這確實讓我們能夠在訪問方面一帆風順。增長真的來自——這要歸功於產品的形象，以及我們在美國以及現在日本和德國擴大多發性神經病處方者基礎的努力。

And your next question comes from the line of Myles Minter with William Blair.

你的下一個問題來自 Myles Minter 和 William Blair 的台詞。

Just on the HELIOS-A extension in the 50 mg biannual dosing. Did the 5 patients that passed away in that arm all achieved the 80% TCR knockdown? Or did they not? And did they all die from cardiomyopathy? There just, again, seems to be an imbalance between mortality on the 25 milligram every quarter and the 50 mg biannual, and we know that the 25 mg quarterly is efficacious. So just clarifying that would be helpful.

就在 50 毫克半年一次給藥的 HELIOS-A 擴展上。那隻手臂中去世的 5 名患者是否都實現了 80% 的 TCR 擊倒？或者他們沒有？他們都死於心肌病嗎？同樣，每季度 25 毫克的死亡率與每半年 50 毫克的死亡率之間似乎存在不平衡，我們知道每季度 25 毫克是有效的。所以只是澄清一下會有幫助。

Thanks, Myles. Maybe I can just give you a little bit of context of the death events that happened in this study. I mean just taking a step back, the overall safety in terms of adverse events, serious adverse events, cardiac, renal, hepatic events, laboratories, that was all really quite balanced between the arms. We did see this numerical difference in terms of deaths. They were all unrelated as deemed by the investigator. They had multiple risk factors for poor prognosis in terms of advanced NYHA class, elevated BNP or aggressive mutations.

謝謝，邁爾斯。也許我可以給你一些關於本研究中發生的死亡事件的背景信息。我的意思是退後一步，在不良事件、嚴重不良事件、心臟、腎臟、肝臟事件、實驗室方面的整體安全性，這在手臂之間確實非常平衡。我們確實在死亡方面看到了這種數字差異。調查人員認為他們都是無關的。就晚期 NYHA 分級、BNP 升高或侵襲性突變而言，他們有多種預後不良的危險因素。

As an example, 3 out of the 5 patients in the 50 mg biannual regimen who passed away had Glu 89 Gln and (inaudible) mutations, which are particularly aggressive. That makes the causes to some CV, but some were non-CV. As an example, one of the patients who passed away in the biannual regimen was diagnosed with acute myeloid leukemia and died after chemotherapy. And then we looked -- there was no relationship to pharmacokinetics or as you were asking pharmacodynamics, i.e., knockdown that we observed. So we'll provide more details in an upcoming scientific meeting. But we're very reassured from the detailed safety now is just not, to our mind, seemed to be any relationship to the drug.

例如，在 50 毫克半年一次方案中去世的 5 名患者中有 3 名有 Glu 89 Gln 和（聽不清）突變，這些突變特別具有侵襲性。這使得某些 CV 成為原因，但有些是非 CV。例如，在半年一次的治療方案中去世的一名患者被診斷出患有急性髓系白血病，並在化療後死亡。然後我們看了——與藥代動力學沒有關係，或者你問的是藥效學，即我們觀察到的擊倒。因此，我們將在即將召開的科學會議上提供更多細節。但我們對詳細的安全性感到非常放心，在我們看來，現在似乎與藥物沒有任何關係。

And your next question comes from the line of Joseph Stringer from Needham & Co.

你的下一個問題來自 Needham & Co. 的 Joseph Stringer。

This is Barbara on for Joey. And our question is about the big picture. Can you give us a sense of what you think ONPATTRO and AMVUTTRA's combined market penetration of the TTR polyneuropathy and mixed phenotypes at this time?

這是喬伊的芭芭拉。我們的問題是關於大局的。您能否告訴我們您對 ONPATTRO 和 AMVUTTRA 目前對 TTR 多發性神經病和混合表型的聯合市場滲透的看法？

Yes, I think just kind of taking a step back and thinking about the market as a whole, I mean, there's no doubt that it's a rapidly growing market with increased physician awareness, increased diagnosis of patients and obviously that translating into increased treatment of patients. So we're very excited that we have 2 RNAi therapeutics and participating and helping patients who have TTR amyloidosis at the moment with polyneuropathy and then, of course, hoping to extend the label to patients who also have cardiomyopathy.

是的，我想退後一步，從整體上考慮市場，我的意思是，毫無疑問，這是一個快速增長的市場，醫生意識提高，患者診斷增加，顯然轉化為患者治療增加.因此，我們很高興我們有 2 種 RNAi 療法，參與並幫助目前患有 TTR 澱粉樣變性多發性神經病的患者，當然，希望將標籤擴展到也患有心肌病的患者。

We think it's a market that also has room for multiple players. It really is all about kind of market growth rather than market share. And I think what's particularly pertinent with respect to our portfolio is we really see our portfolio driving growth overall going forward for Alnylam. So we're very pleased with our progress, thus far, and we look to continue helping physicians treat patients as appropriate with both ONPATTRO and AMVUTTRA. I mean, Tolga, is there anything you want to add in terms of just stepping back and thinking about the TTR market?

我們認為這是一個可以容納多個參與者的市場。這真的是關於某種市場增長而不是市場份額。我認為與我們的投資組合特別相關的是，我們確實看到我們的投資組合推動了 Alnylam 的整體增長。因此，到目前為止，我們對我們的進展感到非常滿意，我們希望繼續幫助醫生使用 ONPATTRO 和 AMVUTTRA 適當地治療患者。我的意思是，Tolga，就退一步思考 TTR 市場而言，你有什麼想補充的嗎？

Yes. Yes, I mean, along the same lines, we're very pleased to be able to provide. Now we do have a franchise. We have 2 products that are available in the U.S. and soon for the rest of the world in polyneuropathy. And what we know is despite the fact that it's a rare disease, there is still significant unmet need. It's a devastating disease. If the patients are not treated, they do end up with mortality and morbidity in a time frame of 5 to 7 years. And despite that, the diagnosis and treatment is still relatively low numbers.

是的。是的，我的意思是，沿著同樣的思路，我們很高興能夠提供。現在我們確實有特許經營權。我們有 2 種產品在美國有售，很快將在世界其他地區用於治療多發性神經病。我們所知道的是，儘管它是一種罕見疾病，但仍有大量未滿足的需求。這是一種毀滅性的疾病。如果不對患者進行治療，他們最終會在 5 到 7 年的時間範圍內死亡和發病。儘管如此，診斷和治療的人數仍然比較少。

And what AMVUTTRA launch has demonstrated to us is the fact that having a very compelling product profile and with the convenience of subcutaneous injectable every quarter really does change the game in terms of how it allows us to be able to reach more patients through by actually finding more physicians. So we do have this prevalence number that's anywhere between 40,000 to 50,000 across the world, including the mix genotype patients. We're still scratching the surface, and as Yvonne indicated, with these products coming into the market, it will allow us to actually increase the awareness, both on the physician side as well as on the patient side and the most recent launch of which clearly demonstrates that.

AMVUTTRA 的推出向我們展示了這樣一個事實，即擁有非常引人注目的產品概況以及每季度皮下注射的便利性確實改變了遊戲規則，它使我們能夠通過實際發現來接觸更多患者更多的醫生。因此，我們確實擁有全世界 40,000 至 50,000 之間的患病率數字，包括混合基因型患者。我們仍在觸及表面，正如 Yvonne 指出的那樣，隨著這些產品進入市場，它將使我們真正提高意識，無論是在醫生方面還是在患者方面，最近推出的清楚地證明了這一點。

Thanks, Tolga. So we've got time for one last question.

謝謝，托爾加。所以我們有時間回答最後一個問題。

And your last question comes from the line of Ellie Merle with UBS.

你的最後一個問題來自瑞銀集團的 Ellie Merle。

Just on the ONPATTRO adcom. I guess just from the interactions and feedback from the FDA so far, do you get the sense that this adcom is more specific to the APOLLO-B data such as being at 12 months? Or do you think it's sort of more broadly about the ATTR landscape in cardiomyopathy and the clinical significance in different subgroups? And I mean, I guess, like in other words, how much do you think the adcom would impact AMVUTTRA's potential labeling discussion versus this being more of an APOLLO-B-specific related discussion at the adcom?

就在 ONPATTRO 廣告上。我想從 FDA 到目前為止的互動和反饋來看，你是否覺得這個 adcom 更具體地針對 APOLLO-B 數據，例如 12 個月？還是您認為它更廣泛地涉及心肌病中的 ATTR 景觀以及不同亞組的臨床意義？我的意思是，我想，換句話說，你認為 adcom 會對 AMVUTTRA 的潛在標籤討論產生多大影響，而這更像是 adcom 上與 APOLLO-B 相關的討論？

Thanks, Ellie, for your question. Again, as we've said at the beginning, we don't have any particular feedback from the agency on the specifics of what the adcom will be or the questions there. And we certainly look forward to hearing more from the agency. We're committed to supporting their review in any way we can. I do expect that the adcom is going to be focused on the APOLLO-B data. However, that's the sNDA that we filed, and that would be the subject of the review. That would also be the data that we'd be sharing and talking about in the context of that the review and the advisory committee as well. But again, we'll look forward to seeing more from the agency when they get back to us with details.

謝謝，艾莉，你的問題。同樣，正如我們在開始時所說的那樣，我們沒有從該機構那裡得到任何關於 adcom 的具體內容或那裡的問題的具體反饋。我們當然期待從該機構聽到更多信息。我們致力於盡我們所能支持他們的審查。我確實希望 adcom 將專注於 APOLLO-B 數據。然而，那是我們提交的 sNDA，這將是審查的主題。這也將是我們在審查和諮詢委員會的背景下共享和討論的數據。但同樣，當他們向我們提供詳細信息時，我們將期待從該機構看到更多信息。

Yes. And again, I think just to underscore, though, that we believe the APOLLO-B data actually has demonstrated a hypothesis that RNAi therapeutics can have a meaningful impact on patients with TTR amyloidosis with cardiomyopathy.

是的。不過，我想再次強調，我們相信 APOLLO-B 數據實際上已經證明了一個假設，即 RNAi 療法可以對患有 TTR 澱粉樣變性心肌病的患者產生有意義的影響。

So we shall stop there. Thank you, everybody, for joining the call. We're really happy with the progress that we've made in the fourth quarter and the full year 2022. We delivered strong commercial results. We've continued to advance our diverse pipeline of programs in development. And we've also got a number of exciting catalysts on track in 2023. So we look forward to updating you along the way as we continue to deliver on these goals. So thank you, everybody, and have a great day.

所以我們就此打住。謝謝大家加入電話會議。我們對第四季度和 2022 年全年取得的進展感到非常高興。我們取得了強勁的商業成果。我們繼續推進我們多樣化的開發計劃。在 2023 年，我們還有許多令人興奮的催化劑。因此，在我們繼續實現這些目標的過程中，我們期待著為您提供最新信息。謝謝大家，祝你有美好的一天。

This concludes today's conference. Thank you for your participation. You may now disconnect.

今天的會議到此結束。感謝您的參與。您現在可以斷開連接。