Alnylam Pharmaceuticals Inc (ALNY) 2023 Q4 法說會逐字稿

Good day, and thank you for standing by. Welcome to the Alnylam Pharmaceuticals Q4 2023 Earnings Conference Call. (Operator Instructions). After the speaker's presentation, there will be a question-and-answer session. Please be advised that today's conference is being recorded. I would now like to hand the conference call over to the company.

美好的一天，感謝您的支持。歡迎參加 Alnylam Pharmaceuticals 2023 年第四季財報電話會議。 （操作員說明）。演講者演講結束後，將進行問答環節。請注意，今天的會議正在錄製中。我現在想把電話會議交給公司。

Good morning. I'm Christine Lindenboom, Senior Vice President of Investor Relations and Corporate Communications at Alnylam.

早安.我是 Christine Lindenboom，Alnylam 投資者關係和企業傳播資深副總裁。

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. Also on the line and available for Q&A is Akshay Vaishnaw, Chief Innovation Officer.

今天與我在一起的有執行長伊馮‧格林斯特里特 (Yvonne Greenstreet)； Tolga Tanguler，首席商務官； Pushkal Garg，首席醫療官；和財務長傑夫·波爾頓。首席創新長 Akshay Vaishnaw 也在線上接受問答。

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.

對於那些透過電話會議參加的人，可以透過造訪我們網站 Investors 頁面的「Events」部分來存取隨附的幻燈片：investors.alnylam.com/events。

During today's call as outlined on Slide 2, Yvonne will offer some introductory remarks and provide 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 for your questions.

在投影片 2 中概述的今天的電話會議中，Yvonne 將發表一些介紹性言論並提供一般背景。托爾加將提供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 將審查我們的財務狀況和指導，然後在我們開始徵求您的問題之前總結即將到來的里程碑。

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 of the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in our most recent periodic report on file with the SEC.

我想提醒您，本次電話會議將包含有關Alnylam 未來期望、計劃和前景的評論，這些評論構成了出於1995 年《私人證券訴訟改革法案》安全港條款目的的前瞻性陳述。實際結果可能存在重大差異這些前瞻性陳述所指出的結果是由於各種重要因素造成的，包括我們向美國證券交易委員會提交的最新定期報告中討論的因素。

In addition, any forward-looking statements represent our views only as of the date of this recording and should not be relied upon as representing our views as of any subsequent date. We specifically disclaim any obligation to update such statements. With that, I'll turn the call over to Yvonne. Yvonne?

此外，任何前瞻性陳述僅代表我們截至本紀錄之日的觀點，不應被視為代表我們在任何後續日期的觀點。我們特別聲明不承擔更新此類聲明的義務。這樣，我就把電話轉給伊馮。伊馮娜？

Thanks, Christine, and thank you, everyone, for joining the call today. Alnylam made great strides in 2023, delivering strong progress across all areas of our business. This includes the robust product growth for our 4 wholly earned commercial medicines, delivering $1.24 billion in global net product revenues and hitting the remarkable milestone of over 5,000 patients now on an Alnylam commercial RNAi therapeutic.

謝謝克里斯汀，也謝謝大家今天加入電話會議。 Alnylam 在 2023 年取得了長足進步，在我們業務的所有領域都取得了強勁進展。這包括我們 4 種完全獲利的商業藥品的強勁產品成長，帶來了 12.4 億美元的全球淨產品收入，並達到了目前超過 5,000 名患者正在接受 Alnylam 商業 RNAi 治療的非凡里程碑。

We have also extended our leadership in our RNAi, including the first-ever demonstration of RNAi-mediated target gene silencing of a human brain and preclinical data showing for the first time delivery of RNAi therapeutics to adipose and muscle tissues. Zilebesiran also made exciting progress for hypertension with encouraging results in the KARDIA-1 Phase II study. Further with zilebesiran, we strengthened our business for the future through business development with a landmark collaboration with Roche.

我們也擴大了我們在 RNAi 領域的領先地位，包括首次展示 RNAi 介導的人類腦標靶基因沉默，以及臨床前數據首次顯示 RNAi 療法可遞送至脂肪和肌肉組織。 Zilebesiran 在高血壓方面也取得了令人興奮的進展，在 KARDIA-1 II 期研究中取得了令人鼓舞的結果。此外，透過與 zilebesiran 的合作，我們透過與羅氏的里程碑式合作進行業務發展，加強了我們未來的業務。

Looking forward, we're excited to continue this progress in 2024, delivering continued commercial execution, notable clinical trial readouts and advancing programs across all stages of development. As you're aware, a key clinical milestone anticipated this year is the readout from our HELIOS-B Phase III study of vutrisiran in patients with ATTR amyloidosis with cardiomyopathy.

展望未來，我們很高興能夠在 2024 年繼續取得這項進展，提供持續的商業執行、顯著的臨床試驗結果並在所有開發階段推進專案。如您所知，今年預期的一個關鍵臨床里程碑是我們針對 ATTR 澱粉樣變性心肌病變患者的 vutrisiran HELIOS-B III 期研究結果。

As we indicated in our press release this morning, we're announcing a few updates to the analysis plan that we believe will enhance the study, enable the best demonstration of vutrisiran's impact across the entirety of the patient population and supports a strong and competitive label. Pushkal will walk through these updates in detail later in the call.

正如我們今天早上在新聞稿中指出的那樣，我們宣布了對分析計劃的一些更新，我們相信這些更新將加強研究，能夠最好地展示vutrisiran 對整個患者群體的影響，並支持強大且有競爭力的標籤。普什卡爾將在稍後的電話會議中詳細介紹這些更新。

We believe all of this puts us on track with our Alnylam P5 by 25 goals, making Alnylam a top-tier biotech developing and commercializing transformative medicines for patients around the world with rare and prevalent diseases driven by a high-yielding pipeline, the first and/or best-in-class product candidates from our organic product engine, all while delivering exceptional financial results. With that, let me now turn the call over to Tolga for a review of our commercial performance. Tolga?

我們相信，所有這些都使我們朝著Alnylam P5 的25 個目標邁進，使Alnylam 成為頂級生物技術公司，為世界各地患有罕見和流行疾病的患者開發和商業化變革性藥物，這是由高收益管道推動的，這是第一個也是/或來自我們有機產品引擎的一流候選產品，同時提供卓越的財務業績。現在，讓我將電話轉給托爾加，以審查我們的商業表現。托爾加？

Thanks, Yvonne, and good morning, everyone. Q4 was another strong quarter for our commercial portfolio with both our TTR franchise and our Ultra rare franchise, delivering growth in excess of 30% compared with Q4 2022. Total net product revenues grew 32% in the fourth quarter versus prior year or 30% at a constant exchange rate as we continue to steadily increase the number of patients on each of our therapies.

謝謝伊馮，大家早安。第四季是我們的商業產品組合的另一個強勁季度，包括我們的TTR 特許經營權和超稀有特許經營權，與2022 年第四季度相比增長超過30%。第四季度產品總淨收入比去年同期成長32%，去年同期成長30%。隨著我們持續穩定增加每種療法的患者數量，匯率保持不變。

Let me now turn to a summary of our fourth quarter TTR performance. Our TTR franchise achieved $254 million in global net product revenues, representing a 10% increase compared with the third quarter and 33% growth compared with the fourth quarter of 2022. At the end of the fourth quarter, more than 4,060 patients were on commercial ONPATTRO or AMVUTTRA treatment worldwide, up from over 3,790 patients at the end of the third quarter, representing 7% quarterly patient growth.

現在讓我總結一下我們第四季的 TTR 表現。我們的 TTR 特許經營權實現了 2.54 億美元的全球產品淨收入，較第三季度增長 10%，較 2022 年第四季度增長 33%。第四季度末，超過 4,060 名患者接受商業 ONPATTRO全球範圍內接受AMVUTTRA 治療的患者數量較第三季末的3,790 多名患者增加，相當於季度患者增加7%。

Now let me provide highlights of our U.S. and international TTR performance. In the U.S., combined sales of ONPATTRO and AMVUTTRA increased by 5% compared with the third quarter and a robust 38% year-over-year driven by AMVUTTRA's launch. The U.S. quarter-over-quarter growth was primarily driven by an increase in demand resulting from the strength of ongoing AMVUTTRA patient uptake, more than offsetting a decrease in ONPATTRO patients switching to AMVUTTRA. At the end of the fourth quarter, more than 85% of U.S. hATTR polyneuropathy patients are now on AMVUTTRA. A testament to its clearly differentiated market-leading profile, including rapid knockdown, reversal of polyneuropathy manifestations, well-established safety profile with thousands of patient years of experience, along with only 4 times a year administration.

現在讓我重點介紹一下我們在美國和國際 TTR 的表現。在美國，ONPATTRO 和 AMVUTTRA 的合併銷售額與第三季相比成長了 5%，在 AMVUTTRA 推出的推動下，年成長了 38%。美國季度環比成長主要是由於 AMVUTTRA 患者持續使用的強勁導致需求增加，足以抵消 ONPATTRO 患者轉用 AMVUTTRA 的減少。截至第四季末，超過 85% 的美國 hATTR 多發性神經病變患者目前正在接受 AMVUTTRA 治療。這證明了其明顯差異化的市場領先地位，包括快速擊倒、逆轉多發性神經病變表現、憑藉數千名患者多年的經驗而建立的良好安全性，以及每年僅需 4 次給藥。

We also continue to progress on increasing our prescriber base which has grown over 50% since AMVUTTRA was launched in the third quarter of 2022. While we've been able to facilitate the development of multidisciplinary center approach for the treatment of hATTR polyneuropathy, driven primarily by cardiologists and neurologists in these centers.

我們也繼續在增加處方者基礎方面取得進展，自2022 年第三季度推出AMVUTTRA 以來，處方者基礎已增長了50% 以上。雖然我們已經能夠促進治療hATTR 多發性神經病的多學科中心方法的開發，但主要推動由這些中心的心臟科醫師和神經科醫師進行。

Now let me turn to our international markets where the TTR franchise growth increased by 18% compared with the third quarter and a strong 28% year-over-year. The quarter-over-quarter growth was driven by the following: demand growth driven by AMVUTTRA's performance, including recent launches in Spain and Italy and continued strong ONPATTRO performance in markets where AMVUTTRA is not yet available, an improvement in gross to net deductions in the quarter following price reductions in Q3, primarily in Germany that were highlighted on our Q3 call; lastly, consistent with our prior years, growth in the fourth quarter was also favorably impacted by increased inventories in Japan and the timing of orders in various partner markets.

現在讓我談談我們的國際市場，與第三季相比，TTR 特許經營成長了 18%，比去年同期成長了 28%。季度環比成長的推動因素如下： AMVUTTRA 的業績推動需求成長，包括最近在西班牙和義大利推出的產品以及在尚未推出 AMVUTTRA 的市場中持續強勁的 ONPATTRO 業績、第三季降價後的一個季度，主要是在我們第三季電話會議上強調的德國；最後，與往年一樣，第四季的成長也受到日本庫存增加和各個合作夥伴市場訂單時間的有利影響。

In summary, AMVUTTRA with its market-leading profile is now available and reimbursed in all major markets across the U.S., Canada, Europe and Japan, driving robust patient and revenue growth in 2023, and we believe we are well positioned for future growth.

總而言之，具有市場領先地位的 AMVUTTRA 現已在美國、加拿大、歐洲和日本的所有主要市場上市並報銷，推動 2023 年患者和收入的強勁增長，我們相信我們已為未來的增長做好了準備。

Moving to our Ultra-Rare franchise. GIVLAARI and OXLUMO delivered $92 million in combined product sales during the fourth quarter representing an 11% increase compared with the third quarter and a solid 30% growth compared with the fourth quarter of 2022. We ended the quarter with more than 1,080 patients on our 2 Ultra-Rare products with approximately 650 patients on GIVLAARI and approximately 430 patients on OXLUMO, representing an 8% combined quarterly growth in patients on our ultra-rare products compared with the third quarter of 2023.

轉向我們的超稀有特許經營權。 GIVLAARI 和OXLUMO 在第四季度的綜合產品銷售額為9,200 萬美元，與第三季相比成長11%，與2022 年第四季相比穩定成長30%。本季末，我們的2 號病患超過1,080 名。超稀有產品約有 650 名患者使用 GIVLAARI，約 430 名患者使用 OXLUMO，與 2023 年第三季度相比，使用我們超稀有產品的患者數量季度綜合增長了 8%。

For GIVLAARI, product sales increased by 10% in Q4 compared with the third quarter, with the following regional dynamics. A 7% increase in U.S. primarily driven by a higher net price achieved in the quarter due to favorable gross to net adjustments, a 16% increase in our international markets, driven by continued demand growth, timing of orders in partner markets and favorable gross to net adjustments.

對於 GIVLAARI 來說，第四季的產品銷售額較第三季成長了 10%，區域動態如下。美國成長7%，主要是由於本季淨價上漲，這是由於有利的總淨值調整所致；在需求持續成長、合作夥伴市場的訂單時機以及有利的總淨值調整的推動下，我們的國際市場增長了16%。淨調整。

For OXLUMO, well positioned as the market-leading therapy in PH1, we delivered a robust 14% increase in product sales compared with the third quarter, which was driven by the following: a 9% increase in the U.S. driven by demand growth, a 16% increase in our international markets, driven by increased demand and the timing of orders in our partner markets.

對於 OXLUMO 來說，作為 PH1 領域的市場領先療法，我們的產品銷售額與第三季度相比強勁增長了 14%，這是由以下因素推動的：美國因需求增長而增長了 9%，由於合作夥伴市場的需求增加和訂單時間安排的推動，我們的國際市場成長了16%。

In conclusion, we're very pleased with the results in the fourth quarter with both our TTR and Ultra-Rare franchises, which delivered strong growth in patients on therapy during the quarter as well as robust year-over-year growth in revenues with both franchises delivering 30% or greater growth versus the fourth quarter of 2022. We are well positioned as we enter 2024 to continue delivering our medicines to more patients in need around the world. Now with that, I will turn it over to Pushkal to review our recent R&D and pipeline progress. Pushkal?

總而言之，我們對 TTR 和 Ultra-Rare 特許經營權第四季度的業績感到非常滿意，這兩個特許經營權在本季度接受治療的患者數量強勁增長，並且收入同比強勁增長與2022 年第四季度相比，特許經營權實現了30% 或更高的增長。進入2024 年，我們已做好充分準備，繼續向世界各地更多有需要的患者提供我們的藥品。現在，我將把它交給 Pushkal 來回顧我們最近的研發和管道進展。普什卡爾？

Thank you, Tolga, and good morning, everyone. I'm going to begin with some important updates that we're announcing this morning regarding HELIOS-B. As you know, HELIOS-B is an outcome study being conducted to expand the label for AMVUTTRA to include the treatment of cardiomyopathy in patients with hereditary and wild-type ATTR amyloidosis. Today, ONPATTRO and AMVUTTRA are approved to treat polyneuropathy in patients with hereditary ATTR amyloidosis with an estimated prevalence of 25,000 to 30,000 patients worldwide.

謝謝托爾加，大家早安。我將從今天早上宣布的有關 HELIOS-B 的一些重要更新開始。如您所知，HELIOS-B 是一項結果研究，旨在擴大 AMVUTTRA 的標籤，以包括治療遺傳性和野生型 ATTR 澱粉樣變性患者的心肌病變。如今，ONPATTRO 和 AMVUTTRA 被批准用於治療遺傳性 ATTR 澱粉樣變性患者的多發性神經病變，估計全球有 25,000 至 30,000 名患者患病率。

Assuming successful results from the HELIOS-B study and regulatory approval, we expect to expand into a market approximately 10x larger with a global prevalence greater than 300,000 patients. And furthermore, we're committed to continuing to innovate from patients with this disease as we advance ALN-TTRsc04, another medicine that can deliver rapid knockdown with the potential for greater efficacy and once annual dosing through clinical development.

假設 HELIOS-B 研究取得成功並獲得監管部門批准，我們預計將擴展到約 10 倍大的市場，全球患病率超過 30 萬名患者。此外，隨著我們推進ALN-TTRsc04，我們致力於繼續從患有這種疾病的患者身上進行創新，ALN-TTRsc04 是另一種可以快速擊倒的藥物，具有更大功效的潛力，並且透過臨床開發每年給藥一次。

Moreover, as illustrated in this graphic for the United States, we expect this already sizable market to continue to grow substantially in the coming years due to increasing disease awareness, earlier diagnosis and the availability of new treatments. Just given these dynamics, we are laser-focused on bringing our industry-leading portfolio of potentially transformative therapeutics to ATTR-CM patients and being leaders in this important growth category.

此外，正如這張美國圖表所示，由於疾病意識的提高、早期診斷和新療法的出現，我們預計這個已經相當大的市場在未來幾年將繼續大幅增長。鑑於這些動態，我們專注於為 ATTR-CM 患者帶來業界領先的潛在變革性治療藥物組合，並成為這一重要成長類別的領導者。

Now as we previously highlighted, between now and tafamidis loss of exclusivity anticipated in late 2028, we expect the market to be primarily monotherapy-driven given the cumulative costs of combination therapy. Our research with payers has confirmed that they plan to restrict combination use, given that it would drive substantially higher cost. And even today, with tafamidis and AMVUTTRA have nonoverlapping labels, about 90% of commercial plans restrict combination use.

正如我們之前強調的那樣，從現在到預計 2028 年底 tafamidis 失去排他性，考慮到聯合治療的累積成本，我們預計市場將主要由單一療法驅動。我們對付款人的研究證實，他們計劃限制組合使用，因為這會大幅提高成本。即使在今天，tafamidis 和 AMVUTTRA 的標籤不重疊，約 90% 的商業計劃限制組合使用。

More importantly, we've seen very limited instances in which 2 branded rare disease products are used in combination regardless of the therapeutic area. Assuming positive data from HELIOS-B and regulatory approval, we anticipate that vutrisiran has the potential product profile, including compelling efficacy, safety and a quarterly subcu dosing regimen to become primarily a first-line treatment for newly diagnosed ATTR-CM patients and a switch therapy for those who experienced disease progression with stabilizers. And to be combined with the stabilizer in those limited situations where payers support access.

更重要的是，我們見過非常有限的情況，其中兩種品牌的罕見疾病產品組合使用，無論治療領域如何。假設來自HELIOS-B 的積極數據和監管部門的批准，我們預計vutrisiran 具有潛在的產品特徵，包括引人注目的功效、安全性和季度subcu 給藥方案，將主要成為新診斷ATTR-CM 患者的一線治療和轉換對那些使用穩定劑經歷疾病進展的患者進行治療。並在付款人支援訪問的有限情況下與穩定器結合使用。

Once tafamidis goes generic and again, pending the label, we believe that combination therapy will become more common. With this backdrop in mind, let's now turn to HELIOS-B, why we're confident, it's poised for success and the endpoint refinements that we are announcing today.

一旦他法米迪成為仿製藥，並再次等待標籤，我們相信聯合療法將變得更加普遍。考慮到這個背景，現在讓我們轉向 HELIOS-B，為什麼我們有信心，它已經做好了成功的準備，以及我們今天宣布的端點改進。

The reasons for our continued confidence are summarized here. The impact of TTR silencing with an RNAi therapeutic on cardiomyopathy was demonstrated in the 12-month APOLLO-B study. We believe these data's are exceedingly informative and support the potential for vutrisiran to demonstrate an outcomes benefit in HELIOS-B. On functional outcomes such as 6-minute walk test as well as quality of life, we saw evidence of disease stabilization over time. We also saw a profound impact on NT-proBnP troponin, which are highly validated indicators of disease severity and prognosis.

我們持續充滿信心的原因總結如下。為期 12 個月的 APOLLO-B 研究證明了 RNAi 療法沉默 TTR 對心肌病變的影響。我們相信這些數據資訊豐富，並支持 vutrisiran 在 HELIOS-B 中展示結果益處的潛力。在 6 分鐘步行測試等功能結果以及生活品質方面，我們看到了疾病隨著時間的推移而穩定的證據。我們也看到了對 NT-BnP 肌鈣蛋白的深遠影響，它是疾病嚴重程度和預後的高度有效的指標。

These 4 parameters, all of which showed the greatest magnitude of effect in the monotherapy setting are important predictors of cardiovascular outcomes, which we would expect to manifest in a larger and longer study like HELIOS-B. And accordingly, as we shared at AHA last November, we were encouraged to see a favorable trend in mortality that separated beginning as early as 9 months and continuing to expand over 24 months. While not powered for mortality, the hazard ratio at 24 months was 0.67, favoring patisiran and the benefits were seen in both the monotherapy and combination settings.

這 4 個參數在單一療法中顯示出最大的效果，是心血管結局的重要預測因子，我們希望在像 HELIOS-B 這樣的更大、更長的研究中體現出來。因此，正如我們去年 11 月在 AHA 上分享的那樣，我們很高興看到死亡率的有利趨勢，這種趨勢早在 9 個月就開始出現，並在 24 個月內持續擴大。雖然沒有對死亡率進行檢驗，但 24 個月時的風險比為 0.67，有利於 patisiran，並且在單一療法和聯合療法中都可以看到好處。

We find these data very compelling as well APOLLO-B was too short and too small to establish an outcomes benefit and impact on mortality appeared to occur earlier than seen in other ATTR-CM studies to date was durable and in fact, grew over time, despite crossover of all patients to active treatment at 12 months.

我們發現這些數據非常引人注目，而且APOLLO-B 太短太小，無法確定結果效益，而且對死亡率的影響似乎比迄今為止其他ATTR-CM 研究中出現的時間更早，而且是持久的，事實上，隨著時間的推移而增長，儘管所有患者在 12 個月時都交叉接受了積極治療。

Now moving on to HELIOS-B itself. The study is designed and powered to deliver outcomes and is twice as large and 3x as long as APOLLO-B. Previous studies have shown that intervention in ATTR cardiomyopathy most benefits patients with NYHA Class I and II and the HELIOS-B study is enriched specifically for these patients as they're most likely to show the largest treatment effect. And HELIOS-B provides the longest follow-up of any study conducted in ATTR cardiomyopathy to date.

現在轉向 HELIOS-B 本身。研究的設計和動力是為了取得成果，其規模是 APOLLO-B 的兩倍，時間是 APOLLO-B 的三倍。先前的研究表明，對 ATTR 心肌病變的干預最有利於 NYHA I 級和 II 級患者，而 HELIOS-B 研究專門針對這些患者進行了豐富，因為他們最有可能顯示出最大的治療效果。 HELIOS-B 提供了迄今為止針對 ATTR 心肌病變進行的最長的隨訪。

The study was conservatively powered at the outset with additional tailwinds that include over enrollment by 10% and tafamidis baseline and drop-in rates that are below the expectations we used to power the study. In fact, the tafamidis rates at baseline were 40%, substantially less than the 50% we had assumed when powering the study.

研究一開始就採取了保守的態度，並受到了額外的有利因素，包括入組人數超額 10%，tafamidis 基線和下降率低於我們用於支持研究的預期。事實上，基線時的 tafamidis 比率為 40%，大大低於我們在進行研究時假設的 50%。

So putting all this together, we have several key takeaways. First, existing plan restrictions and prior precedents suggest that for the next several years, the market is expected to be primarily monotherapy driven. And second, we have data from APOLLO-B that demonstrate substantial effects on multiple endpoints that provide evidence of a differentiated profile with disease stabilization, along with evidence of an early emerging benefit mortality. And finally, and as expected, the treatment effect in APOLLO-B was shown to be largest in the monotherapy population, which was a dominant population study and best suited to demonstrate the treatment benefits of patisiran.

因此，將所有這些放在一起，我們有幾個關鍵要點。首先，現有的計劃限制和先前的先例表明，未來幾年，市場預計將主要由單一療法驅動。其次，我們有來自 APOLLO-B 的數據，這些數據證明了對多個終點的重大影響，這些終點提供了疾病穩定的差異化特徵的證據，以及早期出現的受益死亡率的證據。最後，正如預期的那樣，APOLLO-B 的治療效果在單一療法人群中表現出最大，這是一項主要人群研究，最適合證明 patisiran 的治療益處。

Today, we are announcing enhancements to the HELIOS-B statistical plan to optimize the study for success and a strong and competitive label. These changes are informed by the insights from the APOLLO-B data and emerging data from the field. With these optimizations, we remain focused on clinical outcomes of death and hospitalization, which are critical to all stakeholders.

今天，我們宣布增強 HELIOS-B 統計計劃，以優化研究以取得成功並提供強大且有競爭力的標籤。這些變化是根據 APOLLO-B 數據和現場新數據的見解得出的。透過這些優化，我們仍然關注死亡和住院的臨床結果，這對所有利害關係人至關重要。

The plan to evaluate this in the overall population as well as the monotherapy population which is expected to have the largest treatment effect and best demonstrate the drug's true impact. We also are focusing the secondary endpoint structure on critical clinical elements that highlight the drug's potentially differentiated profile and its benefits on stabilization of this progressive disease. And we are enhancing the overall statistical powering of the study by incorporating up to an additional 3 months of event collection at the tail end of the study period. The most critical period and firmly establishing HELIOS-B as the longest placebo-controlled study conducted to date in ATTR-CM.

該計劃在總體人群以及單一療法人群中進行評估，預計將產生最大的治療效果並最好地證明該藥物的真正影響。我們也將次要終點結構重點放在關鍵的臨床要素上，這些要素強調了該藥物的潛在差異化特徵及其對穩定這種進行性疾病的益處。我們正在透過在研究期末納入最多 3 個月的事件收集來增強該研究的整體統計能力。這是 ATTR-CM 迄今為止進行的最關鍵的時期，並牢牢確立了 HELIOS-B 為最長的安慰劑對照研究的地位。

Let me review the key changes one by one. First, we're sharing today that we are increasing the minimum follow-up in the study from 30 to 33 months with variable follow-up to 36 months. This adds up to 3 months of event collection for the patients who enrolled later in the study, they're -- thereby providing greater statistical power.

讓我一一回顧一下關鍵的變化。首先，我們今天要分享的是，我們正在將研究的最短追蹤時間從 30 個月增加到 33 個月，並將可變追蹤時間延長至 36 個月。對於後來加入研究的患者來說，這相當於 3 個月的事件收集，從而提供了更大的統計能力。

With these changes, approximately 60% of patients remaining on study will have greater follow-up, with about 20% or 1/3 more having follow-up all the way out to month 36. This is an important change as these 3 additional months of observation constitute a short but meaningful prolongation during the critical late part of the study, which is when we expect to see the greatest number of outcome events happening in the placebo arm.

透過這些變化，大約60% 仍在研究中的患者將獲得更大的隨訪，其中約20% 或1/3 的患者將一直隨訪到第36 個月。這是一個重要的變化，因為這額外的3 個月在研究的關鍵後期階段，觀察的時間構成了短暫但有意義的延長，此時我們期望看到安慰劑組中發生最多數量的結果事件。

As a result, this enhancement leads to greater study power as we know that survival curves typically diverge more and more over time, a phenomenon that was seen in the 24-month APOLLO-B data as well.

因此，這種增強帶來了更大的研究力量，因為我們知道，隨著時間的推移，生存曲線通常會越來越偏離，這種現像在 24 個月的 APOLLO-B 數據中也出現過。

Second, we're modifying the methodology used to analyze the primary endpoint. The primary outcome measure remains the composite of all-cause mortality in recurrent cardiovascular events. This will now be tested in parallel in 2 populations, the overall population and the monotherapy population that is the subgroup of patients not on tafamidis at baseline.

其次，我們正在修改用於分析主要終點的方法。主要結局指標仍然是複發性心血管事件的全因死亡率的綜合指標。現在將在 2 個人群中並行測試，即總體人群和單一治療人群（基線時未服用他法米迪的患者亞組）。

We're maintaining the analysis in the overall population, which has the largest sample size and an opportunity to show a broad effect across the full patient spectrum. We're confident that there is a combo effect as demonstrated by the fact that the overall population remains in the primary end point. In parallel, we're elevating an analysis of the composite in the monotherapy population, which constitutes the majority of the study population at 60%. Additionally, the analysis in the monotherapy population allows us to demonstrate the true impact of vutrisiran as a stand-alone treatment, providing a data set that will be particularly relevant to patients, prescribers and others as it closely aligns with where we see the treatment landscape over the next several years.

我們正在維持對總體人群的分析，該人群具有最大的樣本量，並且有機會在整個患者範圍內顯示廣泛的影響。我們相信存在組合效應，正如總體人群仍處於主要終點這一事實所證明的那樣。同時，我們正在對單一療法族群進行綜合分析，該族群佔研究族群的大多數，佔 60%。此外，對單一療法人群的分析使我們能夠證明 vutrisiran 作為獨立治療的真正影響，提供與患者、處方者和其他人特別相關的數據集，因為它與我們對治療前景的看法密切相關在接下來的幾年裡。

It's important to note that these are not co-primary endpoints. Rather primary endpoint will be tested in parallel in both populations such that if each p-value is less than or equal to 0.05 and statistical significance can be claimed for both. Alternatively, the study will be declared a positive study either of the p-values for the 2 analyses is less than or equal to 0.025. This study will be deemed positive in both or either of the analyses achieved the predefined criteria for statistical significance.

值得注意的是，這些不是共同主要終點。相反，主要終點將在兩個人群中並行測試，這樣如果每個 p 值小於或等於 0.05，則可以聲稱兩者俱有統計顯著性。或者，如果 2 項分析的 p 值小於或等於 0.025，則該研究將宣佈為陽性研究。這項研究將被視為陽性，其中兩項或其中一項分析達到了統計顯著性的預定標準。

Based on our assumptions, as informed by APOLLO-B and other studies as well as the conduct and execution of HELIOS-B, we remain confident about HELIOS-B and its ability to deliver a positive result.

根據我們的假設，根據 APOLLO-B 和其他研究以及 HELIOS-B 的實施和執行，我們對 HELIOS-B 及其產生積極結果的能力仍然充滿信心。

Finally, we've streamlined the secondary endpoints. Specifically, the structure now includes 6-minute walk test, KCCQ OS, all-cause mortality and change from baseline and NYHA class. These endpoints are considered clinically meaningful and will help to demonstrate the impact of vutrisiran on disease stabilization and including them as formal secondary endpoints, enables them to potentially be included in the label and support differentiation in the marketplace.

最後，我們簡化了次要端點。具體來說，該結構現在包括 6 分鐘步行測試、KCCQ OS、全因死亡率以及相對於基線和 NYHA 等級的變化。這些終點被認為具有臨床意義，將有助於證明 vutrisiran 對疾病穩定的影響，並將它們作為正式的次要終點，使它們有可能被包含在標籤中並支持市場上的差異化。

Based on the 3 optimizations I've just outlined, here is the updated study design. I do want to note that the changes I've shared today were made after consultation with the FDA and other health authorities. We're supportive of this approach, particularly as it relates to the handling of the primary end point. With the 3-month extension in the overall study duration we are sharing today the top line results are now expected in late June or early July.

基於我剛剛概述的 3 項優化，以下是更新的研究設計。我確實想指出，我今天分享的更改是在與 FDA 和其他衛生當局協商後做出的。我們支持這種方法，特別是因為它涉及主要終點的處理。隨著整個研究持續時間延長 3 個月，我們今天分享的主要結果預計將在 6 月底或 7 月初公佈。

At that time, we plan to provide p-values on the primary and secondary end points as well as key details regarding safety. We also expect to provide some high-level information on subgroups, including patients on baseline tafamidis. Full results are expected to be presented at a scientific congress soon thereafter. Assuming positive results from HELIOS-B, we expect to submit a supplemental NDA to the FDA in late 2024.

屆時，我們計劃提供主要和次要終點的 p 值以及有關安全性的關鍵細節。我們還希望提供一些有關亞組的高級信息，包括使用基線 tafamidis 的患者。預計完整結果將在不久後的科學大會上公佈。假設 HELIOS-B 取得正面結果，我們預計在 2024 年底向 FDA 提交補充 NDA。

We're confident that the study updates I've just reviewed. Refinements to endpoints and extension of the blinded study period further enhance the power of the study and our confidence that HELIOS-B will deliver a positive result.

我們對我剛剛審查的研究更新充滿信心。終點的完善和盲法研究期的延長進一步增強了研究的力量，也增強了我們對 HELIOS-B 將帶來正面結果的信心。

Assuming positive data and regulatory approval, we believe that vutrisiran will be well positioned to serve patients with ATTR cardiomyopathy, addressing unmet needs with the potential for a highly competitive market-leading profile, including a unique mechanism of action that works upstream of protein production and enables rapid knockdown of TTR, and impactful clinical profile with the potential to reduce mortality and CV hospitalization and help be an exorable decline in functional capacity and quality of life, an attractive quarterly dosing schedule that aligns with physician visits, support strong adherence and provide the flexibility of in-office or at-home dose administration.

假設積極的數據和監管部門的批准，我們相信vutrisiran 將處於有利地位，為ATTR 心肌病變患者提供服務，解決未滿足的需求，並有可能形成高度競爭的市場領先地位，包括在蛋白質生產和上游發揮作用的獨特作用機制。能夠快速降低TTR 和具有影響力的臨床特徵，有可能降低死亡率和心血管住院率，並有助於功能能力和生活品質的嚴重下降，這是一個有吸引力的季度給藥方案，與醫師就診一致，支持強烈的依從性，並提供辦公室或家庭劑量管理的靈活性。

And favorable payer dynamics, where coverage under Medicare Part B is expected to result in the majority of patients having 0 out-of-pocket costs and where we also expect payers to favor monotherapies for the next several years.

以及有利的付款人動態，醫療保險 B 部分的承保範圍預計將使大多數患者的自付費用為零，我們也預計付款人在未來幾年將青睞單一療法。

We look forward to sharing top line results from HELIOS-B in the late June to early July time frame, bringing this transformative medicine one step closer to patients.

我們期待在 6 月底至 7 月初的時間範圍內分享 HELIOS-B 的主要結果，讓這種變革性藥物更接近患者。

Let me now turn to some recent and exciting developments with ALN-APP in development for the treatment of Alzheimer's disease and cerebral amyloid angiopathy. The early clinical data from this program continue to be very encouraging. At CTAD, we presented data showing that single doses of ALN-APP achieved sustained pharmacodynamic activity up to 10 months after administration with marked reductions in A beta 42 and A beta 40. Amyloid fragments implicated in Alzheimer's disease and CAA, respectively, as well as an encouraging safety profile.

現在讓我談談 ALN-APP 在治療阿茲海默症和腦澱粉樣血管病變方面的一些最新進展。該計劃的早期臨床數據仍然非常令人鼓舞。在CTAD 上，我們提供的數據顯示，單劑量的ALN-APP 在給藥後長達10 個月內實現了持續的藥效活性，Aβ42 和Aβ40 顯著降低。澱粉樣蛋白片段分別與阿爾茨海默病和CAA 相關，以及令人鼓舞的安全狀況。

As we announced in our press release today, we are very pleased to share that the FDA has provided clearance to initiate the multi-dose Part B of the Phase I study in the United States. This decision came after we submitted additional nonclinical data as well as emerging clinical data from the ongoing Phase I study. The FDA has confirmed that multiple dosing in the Phase I study may proceed at doses as high as 180 milligrams every 6 months, while a partial clinical hold remains for doses that are higher or more frequent than that.

正如我們今天在新聞稿中宣布的那樣，我們非常高興地宣布 FDA 已批准在美國啟動 I 期研究的多劑量 B 部分。這項決定是在我們提交了額外的非臨床數據以及正在進行的一期研究中出現的臨床數據之後做出的。 FDA 已確認，I 期研究中的多次給藥可能會以每 6 個月高達 180 毫克的劑量進行，而對於更高或更頻繁的劑量，部分臨床仍保留。

We're delighted by the FDA's decision and are encouraged that we will be able to proceed in Phase I with multiple doses at levels up to and even exceeding all the dose levels that we plan to test in Part B of the study based on the high and sustained levels of knockdown that we've already seen with single doses of 75 milligrams in Part A.

我們對 FDA 的決定感到高興，並感到鼓舞的是，我們將能夠以多種劑量繼續進行第一階段，劑量水平達到甚至超過我們計劃在研究 B 部分中基於高劑量測試的所有劑量水平。以及我們在A 部分中單劑量75 毫克已經看到的持續擊倒水平。

Let me now move on to recent -- to highlight recent progress across the rest of the pipeline. For zilebesiran, we presented the cardia Phase II results, which demonstrated over 16 millimeters of placebo-adjusted reduction in 24-hour mean systolic blood pressure at 3 months after a single dose with an encouraging safety and tolerability profile.

現在讓我談談最近的進展——強調其餘管道的最新進展。對於 zilebesiran，我們展示了賁門 II 期結果，結果表明，單次給藥後 3 個月，安慰劑調整後的 24 小時平均收縮壓降低超過 16 毫米，安全性和耐受性令人鼓舞。

On ALN-TTRsc04, we recently shared single dose data, which showed deep and rapid knockdown with mean serum TTR reduction up to 97% with durability supporting the potential for annual dosing.

關於 ALN-TTRsc04，我們最近分享了單劑量數據，該數據顯示深度和快速的敲低，平均血清 TTR 降低高達 97%，並且持久性支持每年給藥的潛力。

We also announced positive initial results from the Phase I study of ALN-KHK with robust target engagement and encouraging safety that supported continued development as a novel treatment for type 2 diabetes. And wrapping up on the pipeline, we announced several exciting updates from our research portfolio at our R&D Day, including progress with extrahepatic delivery of RNAi to muscle and adipose, compelling new targets in areas of high unmet need and advancement of RNAi in oncology with a Phase I study for ALN-BCAT hepatocellular carcinoma on track to initiate early this year. And this progress is accelerating as we plan to file proprietary INDs for 9 programs by the end of 2025 against targets in the liver, CNS, muscle and adipose.

我們也宣布了 ALN-KHK I 期研究的積極初步結果，該研究具有強大的目標參與度和令人鼓舞的安全性，支持作為 2 型糖尿病的新型治療方法的持續開發。最後，我們在研發日宣布了我們的研究組合中的幾項令人興奮的更新，包括肝臟外向肌肉和脂肪遞送RNAi 的進展、在高度未滿足需求的領域中引人注目的新目標以及RNAi 在腫瘤學領域的進展ALN-BCAT 肝細胞癌的 I 期研究預計將在今年年初啟動。隨著我們計劃在 2025 年底針對肝臟、中樞神經系統、肌肉和脂肪目標的 9 個項目提交專有 IND，這一進展正在加速。

If we include partnered programs, we anticipate 15 new INDs by the end of 2025, representing a doubling of the Alnylam clinical pipeline by the end of next year. 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. And with that, let me now turn it over to Jeff to review our financial results and upcoming milestones. Jeff?

如果我們包括合作項目，我們預計到 2025 年底將有 15 個新的 IND，這意味著到明年年底 Alnylam 臨床管道數量將增加一倍。這種非凡而獨特的創新步伐使我們處於有利地位，能夠擁有強大的、自我永續的管道，可以為多個疾病領域的患者帶來有意義的影響。現在，讓我將其交給 Jeff 來審查我們的財務表現和即將到來的里程碑。傑夫？

Thanks, Pushkal. Good morning, everyone. I'm pleased to be presenting Alnylam's Full Year 2023 Financial Results and providing our Financial Guidance for 2024.

謝謝，普什卡爾。大家，早安。我很高興介紹 Alnylam 的 2023 年全年財務表現並提供我們的 2024 年財務指導。

Starting with a summary of our P&L results for the full year. Total product revenues for 2023 were $1.24 billion or 39% growth versus 2022 with both our TTR and Ultra-Rare franchises reporting strong growth of 35% or greater for the full year. The full year net revenue from collaborations was $546 million, representing more than a fourfold increase compared with 2022, with the increase being primarily driven by revenue recognized under our co-development and co-commercialization collaboration with Roche, as executed in July 2023.

首先總結我們全年的損益結果。 2023 年的產品總收入為 12.4 億美元，比 2022 年增長 39%，其中我們的 TTR 和 Ultra-Rare 特許經營權全年強勁增長 35% 或更高。全年來自合作的淨收入為5.46 億美元，比2022 年增長了四倍多，這一增長主要是由我們與羅氏(Roche) 於2023 年7 月執行的共同開發和共同商業化合作中確認的收入推動的。

Gross margin on product sales was 78% for the full year, representing a 6% decrease compared with 2022, primarily due to increased excess and obsolete charges due to canceling manufacturing commitments and the impairment of ONPATTRO inventory that had been manufactured for future demand associated with the ATTR cardiomyopathy indication for patisiran for which we did not receive regulatory approval in addition to a higher royalty rate payable on net sales of AMVUTTRA.

全年產品銷售毛利率為 78%，較 2022 年下降 6%，主要是由於取消製造承諾導致超額費用和過時費用增加，以及為滿足未來需求而生產的 ONPATTRO 庫存減值。Patisiran 的ATTR 心肌病變適應綜合症，除了AMVUTTRA 淨銷售額應付的更高特許權使用費外，我們尚未獲得監管部門的批准。

Our non-GAAP R&D expenses increased 15% for the full year, primarily related to increased head count and infrastructure related costs to support our growing pipeline and increased clinical costs driven by Cardio 1 and Cardio, 2, two of our Phase II studies in support of our zilebesiran hypertension program.

我們的非公認會計準則研發費用全年增長了15%，主要與支持我們不斷增長的產品線的人員數量和基礎設施相關成本的增加以及由Cardio 1 和Cardio, 2（我們支持的兩項II 期研究）推動的臨床成本增加有關我們的 zilebesiran 高血壓計劃。

Our non-GAAP SG&A expenses increased 6% for the full year, lower than in prior years as we seek to increase the operating leverage associated with our existing commercial and corporate infrastructure. The 6% increase for the year was primarily driven by increased head count related costs and other investments supporting our strategic growth, including the global launch of AMVUTTRA.

我們全年的非 GAAP SG&A 費用增加了 6%，低於往年，因為我們尋求提高與現有商業和企業基礎設施相關的營運槓桿。今年 6% 的成長主要是由於人員數量相關成本的增加以及其他支持我們策略成長的投資（包括 AMVUTTRA 的全球推出）所推動的。

Our non-GAAP operating loss for 2023 was $60 million, representing a nearly $500 million improvement compared with 2022 primarily driven by strong top line results, both in product sales as well as revenue from collaborations, as I previously highlighted. Delivering non-GAAP operating profit by the end of 2025 remains a key focus for the organization per our P5x25 goals.

正如我之前所強調的，我們 2023 年的非 GAAP 營運虧損為 6,000 萬美元，與 2022 年相比減少了近 5 億美元，這主要是由於產品銷售和合作收入方面強勁的營收業績所致。根據我們的 P5x25 目標，到 2025 年底實現非 GAAP 營業利潤仍然是該組織的重點關注點。

Finally, we ended the year with cash, cash equivalents and marketable securities of $2.4 billion compared to $2.2 billion at the end of 2022 with the increase primarily related to the $310 million upfront payment from our zilebesiran co-development, co-commercialization collaboration with Roche, $100 million from Regeneron for achievement of the ALN-APP proof-of-principle milestone and approximately $150 million from employee option exercises, offset by our operating loss for the year. We continue to believe our current cash balance is sufficient to bridge us to a self-sustainable financial profile.

最後，我們年底的現金、現金等價物和有價證券為 24 億美元，而 2022 年底為 22 億美元，成長主要與我們與羅氏共同開發、共同商業化合作支付的 3.1 億美元預付款有關，來自Regeneron的1 億美元用於實現ALN-APP 原理驗證里程碑，約1.5 億美元來自員工選擇權行使，並被我們今年的營運虧損所抵銷。我們仍然相信，我們目前的現金餘額足以幫助我們實現自我可持續的財務狀況。

Now I'd like to turn to our financial guidance for 2024. Starting with net product revenues. We are providing combined net product revenue guidance for ONPATTRO and AMVUTTRA, GIVLAARI and OXLUMO. Our guidance assumes foreign exchange rates as of January 31, 2024, which are noted in the footnote on our guidance slide. We anticipate combined net product revenues for these 4 products will be between $1.4 billion and $1.5 billion, corresponding to a 13% to 21% growth rate at January 31, FX rates.

現在我想談談我們 2024 年的財務指引。從淨產品收入開始。我們為 ONPATTRO 和 AMVUTTRA、GIVLAARI 和 OXLUMO 提供綜合淨產品收入指引。我們的指導假設匯率為截至 2024 年 1 月 31 日的匯率，這在我們的指導幻燈片的腳註中註明。我們預計這 4 種產品的總淨產品收入將在 14 億至 15 億美元之間，相當於 1 月 31 日匯率的 13% 至 21% 成長率。

Consistent with 2023, we are providing constant exchange rate growth guidance for our net product revenues with a projected range of 13% to 21% as well, highlighting no current difference between our guidance using January 31, FX rates and 2023 constant exchange rates.

與 2023 年一致，我們為產品淨收入提供恆定匯率成長指導，預計範圍為 13% 至 21%，這突顯了我們使用 1 月 31 日匯率和 2023 年恆定匯率的指導之間目前沒有差異。

The collaboration and royalty revenue guidance is $325 million to $425 million. We anticipate that collaboration revenue associated with our partnerships with Roche and Regeneron and LEQVIO royalties from Novartis will drive the majority of our collaboration and royalty revenue in 2024. Our guidance for combined non-GAAP R&D and SG&A expenses is a range between $1.675 billion and $1.775 billion, with the midpoint of the guidance range representing 9% growth versus 2023.

合作和版稅收入指引為 3.25 億至 4.25 億美元。我們預計，與羅氏和再生元的合作夥伴關係以及諾華的LEQVIO 特許權使用費將在2024 年推動我們的大部分合作和特許權使用費收入。我們對非GAAP 研發和銷售、一般管理費用合計的指導範圍為16.75 億美元至1.775 美元十億美元，指導範圍的中點代表與 2023 年相比增長 9%。

Growth highlights for R&D expense in 2024 include increased clinical investment in our zilebesiran, TTRsc04 and APP programs 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. As a reminder, reimbursement from partners for R&D OpEx for some partnered programs highlighted by zilebesiran is accounted for as collaboration revenue.

2024 年研發支出的成長亮點包括增加對 zilebesiran、TTRsc04 和 APP 計畫的臨床投資，以及我們臨床前產品組合中 DC 前和 IND 啟動工作的成長，因為我們將繼續投資為未來創造新的有機成長機會。提醒一下，合作夥伴對 zilebesiran 強調的一些合作項目的研發營運支出的報銷被計為協作收入。

Growth highlights for SG&A expense in 2024 include increased medical and commercial investment as we prepare for the potential launch of vutrisiran in the U.S. for ATTR amyloidosis with cardiomyopathy.

2024 年 SG&A 支出的成長亮點包括增加醫療和商業投資，因為我們準備在美國推出 vutrisiran，用於治療 ATTR 澱粉樣變性心肌病變。

Let me now turn from financials and discuss some key goals and upcoming milestones slated for early 2024. We will, of course, be executing on global commercialization of our products, ONPATTRO, AMVUTTRA, GIVLAARI and OXLUMO. We also intend to report top line results from the Cardia 2 phase II study of zilebesiran as well as initiate the Cardia 3 multi-agent combo study.

現在讓我從財務角度討論一些關鍵目標和即將在 2024 年初實現的里程碑。當然，我們將執行我們的產品 ONPATTRO、AMVUTTRA、GIVLAARI 和 OXLUMO 的全球商業化。我們也打算報告 zilebesiran 的 Cardia 2 II 期研究的主要結果，並啟動 Cardia 3 多藥組合研究。

We also expect 3 other trial initiations in early 2024, including the Phase II study of ALN-APP in patients with cerebral amyloid angiopathy, Part B of the Phase I study of ALN-KHK in type 2 diabetes and a Phase I study of ALN-BCAT in hepatocellular carcinoma. And as Pushkal previously noted, we expect to report top line results from the HELIOS-B Phase III study of vutrisiran in late June or early July. Let me now turn it back to Christine to coordinate our Q&A session. Christine?

我們也預期其他3 項試驗將於2024 年初啟動，包括ALN-APP 在腦澱粉樣血管病變患者中的II 期研究、ALN-KHK 在2 型糖尿病中的I 期研究的B 部分以及ALN-KHK 的I 期研究。BCAT 在肝細胞癌中的應用。正如 Pushkal 之前指出的那樣，我們預計將在 6 月底或 7 月初報告 vutrisiran 的 HELIOS-B III 期研究的主要結果。現在讓我把它轉回克里斯汀來協調我們的問答環節。克里斯汀？

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

謝謝你，傑夫。接線員，我們現在可以開始提問。對於那些撥入電話的人，我們想請您將自己限制在每個問題一個問題上，如果您還有其他問題，請回到隊列中。

(Operator Instructions) Our first question comes from the line of Ritu Baral from TD.

（操作員說明）我們的第一個問題來自 TD 的 Ritu Baral。

Quick question on the updated stats analysis. It makes a lot of sense, but I'm wondering about a certain scenario that is outlined on Slide 18 versus some of the proceedings of the APOLLO-B AdComm. If you succeed on the monotherapy population with a p-value of 0.025 only, what has FDA feedback been on this, just given the importance placed on combination therapy and lack of benefit from the prior proceedings? And could that lead to a more restrictive label for the drug versus second line or something based on your interactions on the SAP -- on this final SAP?

關於更新統計分析的快速問題。這很有意義，但我想知道幻燈片 18 中概述的特定場景與 APOLLO-B AdComm 的一些程式的比較。如果您在單一療法族群上取得成功，p 值為 0.025，那麼考慮到聯合療法的重要性以及先前程序中缺乏益處，FDA 對此有何反饋？這是否會導致該藥物相對於二線藥物或基於您在 SAP（最終 SAP）上的互動的更嚴格的標籤？

Thanks, Ritu. That's a great question. And I just want to kind of underscore that we're really confident on the potential effects of vutri will deliver on cardiovascular outcomes. And the HELIOS-B was already well designed and executed to deliver these results. And the changes that we're announcing today enhance an already robust study given how important the study is for patients and for Alnylam.

謝謝，瑞圖。這是一個很好的問題。我只是想強調，我們對 vutri 對心血管結果的潛在影響充滿信心。 HELIOS-B 已經經過精心設計和執行，可以實現這些結果。考慮到這項研究對於患者和 Alnylam 的重要性，我們今天宣布的改變進一步增強了這項本來就很穩健的研究。

And clearly, as Pushkal said, we consulted with the FDA as we made these changes. It's important to note that this is a study that is focused on outcomes, and it's outcomes that are most important to physicians, patients and payers. And that's very different from base scenario assessing endpoints like 6-minute walk test and KCCQ really, if we're able to deliver the primary endpoint as we've described. We're confident that this will be a study that should be approved by health authorities. But happy for Pushkal to add any additional color to that.

顯然，正如普什卡爾所說，我們在做出這些改變時諮詢了 FDA。值得注意的是，這是一項關注結果的研究，而結果對醫生、病人和付款人來說是最重要的。如果我們能夠像我們所描述的那樣提供主要終點，那麼這與 6 分鐘步行測試和 KCCQ 等基本場景評估終點有很大不同。我們相信這將是一項應得到衛生當局批准的研究。但很高興普什卡爾能夠為此添加任何額外的色彩。

No, I think, Yvonne, you've really covered it. Ritu, I think we remain focused on both the overall population. And what we're doing today is highlighting that based on all the learnings from APOLLO-B and in terms of delivering a strong and competitive label and aligning with what is -- where we see the market being for the next several years that we've elevated our analysis of the monotherapy group. And as I mentioned, as Yvonne has highlighted, we've made these adjustments after consultation with FDA and other health authorities. And so we think that will support an approvable package.

不，我想，伊馮，你真的已經涵蓋它了。 Ritu，我認為我們仍然關注整體人口。我們今天所做的事情是強調，基於 APOLLO-B 的所有經驗教訓，提供一個強大且有競爭力的品牌，並與我們認為未來幾年的市場狀況保持一致。提高了我們對單一療法組的分析。正如我所提到的，正如伊馮所強調的那樣，我們在與 FDA 和其他衛生當局協商後做出了這些調整。因此，我們認為這將支持一個可批准的方案。

Our next question comes from the line of Paul Matteis from Stifel.

我們的下一個問題來自 Stifel 的 Paul Matteis。

I totally agree with Ritu that these changes at base makes sense. But I think my main question is why now? It feels like when the study started, we all knew that 33 months is better than 30, that your drug alone would probably have a bigger effect size alone and effect size, that could be a little bit diluted by tafamidis. So what changed? What have you seen in the blinded data? Is there something that's more nuanced here that's leading you to make these changes? And accepting the fact that there's going to be a small delay versus initial guidance?

我完全同意 Ritu 的觀點，即這些變化從根本上來說是有意義的。但我認為我的主要問題是為什麼是現在？感覺就像研究開始時，我們都知道 33 個月比 30 個月好，單獨使用你的藥物可能會產生更大的效果大小，而效果大小可能會被 tafamidis 稍微稀釋。那麼是什麼改變了呢？你在盲數據中看到了什麼？這裡是否有更微妙的因素促使您做出這些改變？並接受這樣一個事實：與最初的指導相比，將會有輕微的延遲？

Thanks, Paul. That's a great question. Look, I mean, these changes were primarily influenced by learnings from APOLLO-B. And important to note, not just the 12-month data, but the open-label extension data at 24 months and beyond. And these data have really informed the enhancements that we've announced today. And I think for us, it's important to make sure we had as much information as we possibly could prior to making any changes before database lock. And also as Pushkal emphasized, to make sure that we consulted with the FDA and other health authorities and that takes time. So I think we're in this sweet spot, if you like, between really understanding all the data that we're going to have prior to database lock and obviously, database lock beyond, which is not possible to make changes.

謝謝，保羅。這是一個很好的問題。看，我的意思是，這些變化主要受到阿波羅-B 的學習影響。值得注意的是，不僅是 12 個月的數據，還有 24 個月及以後的開放標籤擴展數據。這些數據確實為我們今天宣布的增強功能提供了資訊。我認為對我們來說，重要的是要確保在資料庫鎖定之前進行任何更改之前擁有盡可能多的信息。而且正如普什卡爾所強調的那樣，為了確保我們諮詢了 FDA 和其他衛生當局，這需要時間。所以我認為我們正處於這個最佳點，如果你願意的話，在真正了解資料庫鎖定之前我們將擁有的所有資料和顯然資料庫鎖定之後的資料之間是不可能進行更改的。

Yes. I think building on what you said, Yvonne. Paul, I think, look, it makes sense for us to have the maximum amount of information before we make changes to an analysis plan as we're announcing today. These are not changes in the operational conduct of the study, there are to the analytic plan. And again, it makes the most sense to have as much information that's come out of APOLLO-B. We've gotten -- we were in a very fortunate position to run that study and gotten all the information that we did out of that study on a variety of endpoints to have that extended follow-up and then to have the opportunity to align with health authorities.

是的。我認為以你所說的為基礎，伊馮。保羅，我認為，在我們今天宣布的分析計劃發生變化之前，我們擁有盡可能多的信息是有意義的。這些不是研究操作行為的變化，而是分析計畫的變化。再說一遍，擁有盡可能多的來自 APOLLO-B 的信息是最有意義的。我們非常幸運地進行了這項研究，並從該研究中獲得了有關各種終點的所有信息，以便進行長期隨訪，然後有機會與衛生當局。

In the long-term APOLLO-B data, are you seeing a more pronounced monotherapy effect versus an effect on tafamidis, on outcomes and tafamidis-treated patients on outcomes endpoints? Is that part of the nuance here?

在長期 APOLLO-B 數據中，您是否發現單藥治療效果與 tafamidis、結果以及接受 tafamidis 治療的患者在結果終點上的效果相比更明顯？這是這裡細微差別的一部分嗎？

Paul, what I'd say is that what we've seen in the long-term data, and we presented some data last fall at the AdComm and then I think at HFSA are really encouraging to us in both populations, frankly, as it relates to outcomes, right? If you look in the monotherapy group, what we've seen was really sizable effects on a variety of endpoints, as I highlighted in my opening remarks, on a variety of endpoints that predict outcomes.

保羅，我想說的是，我們在長期數據中看到的情況，以及我們去年秋天在AdComm 上提供的一些數據，然後我認為在HFSA 上，坦率地說，對我們這兩個人群來說確實令人鼓舞，因為它與結果有關，對嗎？如果你觀察單一療法組，我們看到的是對各種終點的確實相當大的影響，正如我在開場白中強調的，對預測結果的各種終點的影響。

And we saw a mortality separation. And as we've looked also in the combination group over time, what we saw was favorable effects on outcomes there as well. And so I think both of this just builds into our confidence. But I think certainly, what we're seeing in monotherapy. And again, this is not just APOLLO-B. When we look back at the original APOLLO study, when we look at HELIOS-A, all of this really highlights a very compelling effect. When you look at that overall hazard ratio for mortality was 0.67 at 24 months in the overall population. So we have a lot of confidence in what we're seeing here. And we think these refinements to the analysis plan will only optimize the study for success in getting a strong and competitive label.

我們看到了死亡率的分離。隨著時間的推移，我們也對聯合組進行了研究，我們看到了對結果的有利影響。所以我認為這兩點都增強了我們的信心。但我認為，我們在單一療法中所看到的情況是肯定的。再說一遍，這不僅僅是 APOLLO-B。當我們回顧最初的 APOLLO 研究，當我們觀察 HELIOS-A 時，所有這些確實凸顯了非常引人注目的效果。觀察一下總體人口的 24 個月死亡率總體風險比為 0.67。因此，我們對在這裡看到的情況充滿信心。我們認為對分析計劃的這些改進只會優化研究，從而成功獲得強大且有競爭力的標籤。

Yes. Let me just jump in as well Paul, this is Akshay. I think if we stand back and look just to put some numbers to what Pushkal just mentioned. In APOLLO itself, a hazard ratio for mortality was 0.53. And that showed up as early as 6 months and then the curve started separating.

是的。讓我也插話吧，保羅，我是阿克謝。我想如果我們退後一步，看看普什卡爾剛才提到的一些數字。在 APOLLO 本身，死亡率的風險比為 0.53。這種情況早在 6 個月時就出現了，然後曲線開始分開。

In APOLLO-B, the hazard ratio for mortalities was 0.36 at 12 months, both in the monotherapy as well as with placebo arms. Patisiran 1 is 0.67, as you said at 24 months. And this is now APOLLO-B, that's half the size and changes showing up at 9 months and continue to separate since then.

在 APOLLO-B 中，無論是單一療法或安慰劑組，12 個月時的死亡率風險比均為 0.36。正如您所說，24 個月時 Patisiran 1 為 0.67。這就是現在的 APOLLO-B，大小只有一半，並且在 9 個月時出現變化，並從那時起繼續分離。

So I think the changes we've made today, I'm glad you agree why and a 3-month addition to further increase the robustness of the encouraging data we already see from APOLLO and APOLLO-B, I think just further consolidates that we anticipate a positive study, and we're confident about that. And today's changes just further attest to our confidence in our approach. So I'll leave it at that, but I hope that makes sense to folks.

所以我認為我們今天所做的改變，我很高興你同意為什麼，並且增加了3 個月的時間，以進一步提高我們已經從APOLLO 和APOLLO-B 看到的令人鼓舞的數據的穩健性，我認為只是進一步鞏固了我們預計會有積極的研究，我們對此充滿信心。今天的變化進一步證明了我們對我們的方法的信心。所以我就到此為止，但我希望這對人們來說是有意義的。

Thanks Akshay, that's great. We'll have the next question.

謝謝阿克謝，太棒了。我們將提出下一個問題。

Our next question comes from the line of Ellie Merle from UBS.

我們的下一個問題來自瑞銀集團 (UBS) 的 Ellie Merle。

Can you just elaborate a bit more on the changes you did on the secondary endpoint analysis? Specifically what the hierarchy is of this streamlined secondary endpoint analysis? And what this does for the powering of key secondaries like mortality? And your latest expectation for what we could see on the mortality secondary, particularly in the monotherapy arm?

您能否詳細說明一下您對次要終點分析所做的更改？具體來說，這種簡化的次要終點分析的層次結構是什麼？這對於死亡率等關鍵次要因素有何影響？您對次要死亡率（尤其是單一治療組）的死亡率有何最新期望？

Yes. No, that's a great question, Ellie. And as you note, that we took the decision to streamline the secondary point because we really want to focus on the most clinically important end points to support differentiation. We've seen evidence of disease stabilization and this doesn't appear to be true of evidence generated with stabilizers.

是的。不，這是一個很好的問題，艾莉。正如您所指出的，我們決定簡化次要點，因為我們確實希望專注於臨床上最重要的終點以支持分化。我們已經看到了疾病穩定的證據，但穩定劑產生的證據似乎並非如此。

So we've really been thoughtful about what are the endpoints that focus on important clinical learnings and have therefore removed some of the endpoints from the hierarchical structure, but obviously, we'll be looking at all those data as exploratory endpoints. But Pushkal, perhaps you could just go through a little bit of specific changes that we've made to the secondary endpoints?

因此，我們確實認真考慮了關注重要臨床學習的終點是什麼，因此從層次結構中刪除了一些終點，但顯然，我們將把所有這些數據視為探索性終點。但是 Pushkal，也許您可以回顧一下我們對次要端點所做的一些具體更改？

Yes, absolutely. So Ellie, what we've done is -- obviously, the primary as we talked about, remains a focus on outcomes of death and recurrent CV events that we'll be looking in the 2 populations. Then going down, we put 6-minute walk test in KCCQ next. We think we have ample power for those, and we think those are great endpoints based on what we learned from APOLLO-B to really demonstrate what we seem to see -- be seeing is in terms of differentiated profile. Whereas patients on an RNAi therapeutic appear to have disease stabilization over an extended period of time.

是的，一點沒錯。所以艾莉，我們所做的顯然是，正如我們所討論的，首要任務仍然是關注我們將在兩個人群中觀察的死亡結果和復發性心血管事件。然後下去，我們接下來在KCCQ進行6分鐘步行測試。我們認為我們有足夠的能力來實現這些，我們認為這些是偉大的終點，基於我們從 APOLLO-B 學到的知識，可以真正展示我們似乎看到的東西 - 看到的是差異化的輪廓。而接受 RNAi 治療的患者似乎在很長一段時間內病情穩定。

And while no head-to-head, it looks very different than the progressive decline that we've seen now in 2 pivotal trials with stabilizer therapies. And so we look forward to hopefully seeing those patterns emerge again in HELIOS-B.

雖然沒有正面對比，但它看起來與我們現在在兩個穩定劑療法關鍵試驗中看到的逐漸下降有很大不同。因此，我們期待看到這些模式在 HELIOS-B 中再次出現。

The third endpoint is all-cause mortality. Obviously, that's a higher bar than the primary endpoint. But again, based on what we're seeing and while the study is primarily powered for the composite, we think it's important to be able to demonstrate to look for all-cause mortality. And so we'll be testing that formally in the secondary endpoint structure.

第三個終點是全因死亡率。顯然，這比主要終點更高。但同樣，根據我們所看到的情況，雖然這項研究主要是為綜合數據提供動力，但我們認為能夠證明尋找全因死亡率很重要。因此，我們將在輔助端點結構中正式測試這一點。

And last, we've added an endpoint of NYHA class because we saw some very encouraging data merging out of APOLLO-B that suggested that, again, consistent with an emerging profile that this class of drugs can actually delay disease progression and stabilize the disease that we may see benefits on NYHA class. And we think all of those are clinically important differentiating factors that may -- that we want to make sure that we look at with the potential to include them in the label and differentiate in the marketplace.

最後，我們加入了NYHA 類別的終點，因為我們看到APOLLO-B 合併了一些非常令人鼓舞的數據，這些數據再次表明，與新興的概況一致，即此類藥物實際上可以延緩疾病進展並穩定疾病我們可能會在 NYHA 課程中看到好處。我們認為所有這些都是臨床上重要的差異化因素，我們希望確保我們有潛力將它們納入標籤並在市場上脫穎而出。

Yes. And just building off that last point Pushkal. I think you went through the different endpoints very carefully. From our perspective, we're focusing on the most stringent outcomes, whether it's mortality, hospitalization, quality of life, new hospitalization plus mortality. This is what matters to us. It will show the true impact of this drug and it's what matters to patients and doctors. And ultimately, we hope to get this into the label. And you note that we've avoided putting things like BNP and other endpoints, which we could have put in but we want to focus on the strongest outcomes. And I hope that's a surrogate for the confidence we feel in what we can achieve with vutrisiran. So I'll leave it at that.

是的。就在普什卡爾最後一點的基礎上。我認為您非常仔細地經歷了不同的端點。從我們的角度來看，我們關注的是最嚴格的結果，無論是死亡率、住院、生活品質、新住院加上死亡率。這對我們來說很重要。它將展示這種藥物的真正影響，這對患者和醫生來說都很重要。最終，我們希望將其納入標籤。您注意到，我們避免添加 BNP 和其他端點等內容，我們本來可以添加這些內容，但我們希望專注於最強勁的結果。我希望這能代表我們對 vutrisiran 所能實現的目標充滿信心。所以我就這樣吧。

Next question please.

請下一個問題。

Our next question comes from the line of Kostas Biliouris from BMO Capital Markets.

我們的下一個問題來自 BMO 資本市場的 Kostas Biliouris。

One question from us on the (inaudible) so far HELIOS-B. Looking back at the acoramidis trial. We are wondering whether there was any information there in the readout last year that helped you decide on the changes you are making? And maybe looking forward, how do these changes that you are making help you position AMVUTTRA compared to eplontersen which is reading out next year and also has a well-powered trial.

到目前為止，我們提出了一個關於（聽不清楚）HELIOS-B 的問題。回顧 acoramidis 試驗。我們想知道去年的讀數中是否有任何資訊可以幫助您決定要做出的改變？也許展望未來，您所做的這些改變如何幫助您將 AMVUTTRA 與 eplontersen 相比，eplontersen 將於明年宣讀，並且也有一個強有力的試驗。

Okay. If I heard you correctly, Kostas. I'm trying to understand whether there's any information from the acoramidis study that influenced these changes? And maybe Pushkal, if you can take that question. And then there was a second question around how do these changes influence our views on the commercial opportunity and Tolga, it would be great if you would take that question. So Pushkal?

好的。如果我沒聽錯的話，科斯塔斯。我想了解 acoramidis 研究中是否有任何資訊影響了這些變化？如果你能回答這個問題的話，也許還有普什卡爾。然後還有第二個問題，這些變化如何影響我們對商業機會和托爾加的看法，如果您能回答這個問題，那就太好了。那麼普什卡爾？

Sure. Kostas, I think -- look, I think what was -- a couple of things that we took away from looking at the attribute data that we've talked about in the past. I think first and foremost, I think it's important to note that study as well as APOLLO-B for that matter. Enrolled patients in a contemporary era where we know patients are being diagnosed earlier in their disease through noninvasive means as opposed to what was done in the original ATTR-ACT trial.

當然。科斯塔斯，我認為——看，我認為——我們從過去討論過的屬性數據中得到了一些東西。我認為首先也是最重要的是，我認為重要的是要注意該研究以及 APOLLO-B 的問題。在當代招募的患者中，我們知道患者正在透過非侵入性手段在疾病早期得到診斷，這與最初的 ATTR-ACT 試驗中所做的不同。

And what it showed is that patients in those earlier stages of disease can continue to grow events at a precipitous rate if they're not treated and that an effective therapy can show a benefit on top of that. Second of all, it also showed sort of confirming what was seen in the original ATTR-ACT study that patients with earlier stages of disease like NYHA Class 1 and 2 appear to have the largest magnitude of effect, right?

它表明，處於疾病早期階段的患者如果不接受治療，可能會繼續以急劇的速度發展，而有效的治療可以顯示出除此之外的益處。其次，它也證實了最初 ATTR-ACT 研究中所觀察到的情況，即 NYHA 1 級和 2 級等疾病早期患者似乎具有最大程度的影響，對嗎？

And three, as we've seen in lots of different outcomes trials, not just in this disease, but right, the longer exposure leads to greater separation of curves, right? And so all of those things were learnings that we learned and that patients with -- on stabilizers continue to decline month by month in terms of functional ability and quality of life. And so -- on average.

第三，正如我們在許多不同結果的試驗中看到的那樣，不僅是在這種疾病中，而且暴露時間越長，曲線的分離程度就越大，對嗎？因此，所有這些都是我們學到的教訓，服用穩定劑的患者在功能和生活品質方面繼續逐月下降。平均而言。

And so I think -- all of those are aspects that we look at, again, and sort of we're in -- to help inform some of the choices we made, in particular, but most importantly, it was the APOLLO-B results as well. As we look at them, again, no head-to-head studies, but we see a contrast in terms of the profile that's emerging here of these classes of medicines and the end points and refinements we made really to use the opportunity to extend the double-blind period so that we can increase study power, to optimize the study endpoints -- the primary endpoint structure to allow us to elevate the monotherapy and include secondary endpoints that can elaborate on some of those potential points of differentiation and disease stabilization that these other data sets seem to suggest.

所以我認為——所有這些都是我們再次關注的方面，也是我們所處的領域——以幫助我們做出一些選擇，特別是但最重要的是，這是 APOLLO-B結果也是如此。當我們再次審視它們時，沒有進行頭對頭研究，但我們看到了這些類別藥物的概況以及我們為利用這個機會擴展藥物的終點和改進而進行的對比。雙盲期，以便我們可以提高研究能力，優化研究終點——主要終點結構，使我們能夠提升單一療法的水平，並包括次要終點，這些終點可以詳細說明這些潛在的分化點和疾病穩定點。其他數據集似乎表明了這一點。

Thanks, Pushkal. Great answer. Tolga?

謝謝，普什卡爾。很好的答案。托爾加？

Yes. I mean, as Pushkal indicated, these analytical enhancements obviously makes us very confident and HELIOS-B is able to show added benefit on vutri on top of TAF as well as obviously demonstrating the value of vutrisiran in a pure placebo.

是的。我的意思是，正如 Pushkal 所指出的，這些分析增強顯然讓我們非常有信心，HELIOS-B 能夠在 TAF 的基礎上顯示出 vutri 的額外益處，並明顯證明 vutrisiran 在純安慰劑中的價值。

Now HELIOS-B really empowers us to position AMVUTTRA in a very unique way, both in first on utilization as well as on the switch with the tafamidis until eplontersen comes into market.

現在，HELIOS-B 確實使我們能夠以非常獨特的方式定位 AMVUTTRA，無論是首次使用，還是在 eplontersen 進入市場之前與 tafamidis 的轉換。

A couple of key, I think, attributes that we really need to highlight is the rapid knockdown and sustained knockdown of disease closing protein is very unique to AMVUTTRA. Along with clear outcomes benefit in total population as well as in mono, halting the decline in functional capacity and quality of life, demonstrated years of safety which we have already established with our polyneuropathy indication, attractively sub quarterly dosing and also limited copay burden in patients. These are really going to be unique for AMVUTTRA, which we believe is going to position us a year before potentially even eplontersen coming into the marketplace.

我認為，我們真正需要強調的幾個關鍵屬性是疾病關閉蛋白的快速敲除和持續敲除是 AMVUTTRA 非常獨特的。除了總人口和單一人群的明顯結果獲益之外，阻止了功能能力和生活品質的下降，證明了我們已經通過多發性神經病適應症建立的多年安全性、有吸引力的次季度劑量以及有限的病人自付費用負擔。這些對 AMVUTTRA 來說確實是獨一無二的，我們相信這將使我們比 eplontersen 進入市場早一年定位。

Yes. No, that's great. And just to add that this is in the context of market that is growing really rapidly. And a market where we know that patients who are on current treatments continue to progress. So with the profile that Tolga described, we think we're in a really good position to drive broad commercial uptick of AMVUTTRA and obviously assuming positive results from HELIO-B and approval.

是的。不，那太好了。補充一點，這是在市場成長非常迅速的背景下進行的。我們知道正在接受目前治療的患者在這個市場中不斷取得進展。因此，根據 Tolga 所描述的情況，我們認為我們處於非常有利的位置，可以推動 AMVUTTRA 的廣泛商業成長，並且顯然假設 HELIO-B 取得了積極成果並獲得批准。

And both in first line, as Tolga described, but also switch from stabilized as we've shown how AMVUTTRA has led to a significant switch in the polyneuropathy market. And we anticipate we'll see the same in cardiomyopathy as well with positive data. So I think the changes that we've made, I think, continue to support our confidence in the profile of AMVUTTRA and the potential that will be delivered in the cardiomyopathy market. Next question please?

正如 Tolga 所描述的，兩者都在一線，但也從穩定轉變，正如我們已經展示的 AMVUTTRA 如何導致多發性神經病市場的重大轉變。我們預計在心肌病變中也會看到同樣的情況，並獲得正面的數據。因此，我認為我們所做的改變將繼續支持我們對 AMVUTTRA 的概況及其在心肌病變市場中發揮的潛力的信心。請問下一個問題？

Our next question comes from the line of David Lebowitz from Citi.

我們的下一個問題來自花旗銀行的 David Lebowitz。

In terms of the primary readout, I know historically, you've released p-values as part of the update? Will you be sticking to that plan? Or is there additional data points you might be able to offer in the top line to allow for some level of differentiation between AMVUTTRA and the other therapies?

就主要讀數而言，我知道歷史上您已經發布了 p 值作為更新的一部分？你會堅持這個計畫嗎？或者您可以在頂行提供額外的數據點，以便在 AMVUTTRA 和其他療法之間進行一定程度的區分？

And just kind of attached to that, when you look -- since you're targeting really the front line here with your new analysis plan. What do you actually need in your mind to achieve in the study to be able to unseat tafamidis in the front line? I mean, given that the trials are quite different, and it's not necessarily going to be able to be easy to compare on a head-to-head basis.

當你看的時候，你會有點依戀這一點——因為你的新分析計畫其實是針對前線的。您實際上需要在研究中實現什麼目標，才能在前線取代 tafamidis？我的意思是，考慮到這些試驗有很大不同，並且不一定能夠輕鬆地進行直接比較。

Yes. Just briefly, first question. Look, we'll do what we normally do, and we'll share p values on the primary endpoints and key secondary endpoints as well as some qualitative assessment on safety. We will also present information on subgroups such as the tafamidis subgroups. So I hope that answers that question for you. And Tolga, if you could just very briefly respond to David's question.

是的。簡單來說，第一個問題。看，我們將做我們通常會做的事情，我們將分享主要終點和關鍵次要終點的 p 值以及一些安全性定性評估。我們還將提供有關亞組（例如 tafamidis 亞組）的資訊。所以我希望這能為您解答這個問題。托爾加，請您簡單回答大衛的問題。

Right. Look, we have extensive research that suggests physicians believe 75% of their patients on a stabilizer continue to progress or experience inadequate treatment, which indicates to us that there is a significant remaining unmet need and a sizable potential to switch to AMVUTTRA and particularly prior to the tafamidis [LOE], when payers are implementing already restrictions on combo use. And as Yvonne indicated, we have actually already that great experience starting with ONPATTRO first, and now with AMVUTTRA in ex U.S. markets, where we actually compete with great data.

正確的。看，我們進行了廣泛的研究，表明醫生相信75% 的使用穩定劑的患者會繼續進展或經歷不充分的治療，這向我們表明，仍有大量未滿足的需求，並且有相當大的潛力轉向AMVUTTRA，特別是在使用AMVUTTRA 之前tafamidis [LOE]，當付款人已經實施組合使用限制時。正如 Yvonne 所指出的，我們實際上已經從 ONPATTRO 開始，現在在美國以外市場使用 AMVUTTRA 獲得了很好的經驗，我們實際上在這些市場上與大量數據競爭。

Great. Next question, please.

偉大的。請下一個問題。

Our next question comes from the line of Jessica Fye from JPMorgan.

我們的下一個問題來自摩根大通的 Jessica Fye。

Another one on HELIOS-B. Recognizing that the comparison is going to be versus placebo, what do you want to see in terms of how the event rate in the monotherapy AMVUTTRA patients looks relative to the monotherapy tafamidis patients?

HELIOS-B 上的另一顆。認識到將與安慰劑進行比較，您希望看到單藥治療 AMVUTTRA 患者相對於單藥治療 tafamidis 患者的事件發生率如何？

Yes. Jessica, thanks for the question. Look, I think it's important to note this was not a head-to-head study looking at AMVUTTRA versus tafamidis. This is a study looking at AMVUTTRA or patisiran versus placebo where a proportion of the patients, 40% are on background tafamidis. And so really, the comparisons are AMVUTTRA and placebo in those 2 situations. And as we've said, the primary analysis will be looking at this in the 2 populations, the blended population of overall as well as the monotherapy population.

是的。傑西卡，謝謝你的提問。看，我認為重要的是要注意這不是針對 AMVUTTRA 與 tafamidis 的頭對頭研究。這是一項比較 AMVUTTRA 或 patisiran 與安慰劑的研究，其中 40% 的患者服用背景 tafamidis。事實上，這兩種情況的比較是 AMVUTTRA 和安慰劑。正如我們所說，主要分析將在兩個人群中進行研究，即總體混合人群以及單一治療人群。

Thanks for your question, Jessica. Next question.

謝謝你的提問，潔西卡。下一個問題。

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

我們的下一個問題來自 RBC Capital 的 Luca Issi。

Pushkal actually, if I may, circling back on a prior question, maybe ask a little more directly -- is this informed by blinded event rates tracking below your expectation? And then maybe separately, is this considered a formal protocol amendment? And if so, will you incur any statistical penalties for changing the trial so late in the game? Any color there I much appreciate it.

實際上，如果可以的話，普什卡爾，回到之前的問題，也許可以更直接地問一點——這是由低於您預期的盲事件發生率跟踪得出的嗎？然後也許單獨地，這是否被視為正式的協議修正案？如果是這樣，你會因為在比賽後期改變審判而受到任何統計處罰嗎？任何顏色我都非常欣賞。

Yes. Luca, let me take your second point first. There's no change to the operational conduct of the study. This is just a change in the statistical analysis plan. And we outlined in the slides really how the statistics around the primary endpoints are going to be analyzed. So there's no statistical penalty for that at all. It's just a change to the analytic plan that we've talked about. So no, not at all.

是的。盧卡，讓我先談談你的第二點。該研究的操作行為並沒有改變。這只是統計分析計劃的改變。我們在投影片中概述如何分析主要終點的統計數據。所以根本沒有統計上的懲罰。這只是我們討論過的分析計劃的改變。所以不，一點也不。

And with regard to the first question, I think as trying to highlight the changes are really driven by what we've seen with APOLLO-B over 2-plus years. And the patterns that we're seeing there and our heightened confidence in terms of the impact of this class of medicines on this disease and what we can do to further optimize the study and set it up well for a strong and competitive label.

關於第一個問題，我認為試圖強調這些變化實際上是由我們在 APOLLO-B 上兩年多來所看到的推動的。我們在那裡看到的模式以及我們對此類藥物對這種疾病的影響的信心增強，以及我們可以採取哪些措施來進一步優化研究並為其建立一個強大且有競爭力的標籤。

Of course, we have, as we've said before, have teams that are looking at the blinded data primarily to ensure excellent study conduct and execution, make sure the right patients are enrolled, make sure that the data are clean, make sure that we've got a complete capture of all the events, et cetera. And of course, they're looking at event rates, et cetera. But we're not going to be sharing dribs and drabs the data, and that's not the driver here.

當然，正如我們之前所說，我們有團隊主要研究盲法數據，以確保出色的研究進行和執行，確保招募正確的患者，確保數據乾淨，確保我們已經完整捕獲了所有事件等等。當然，他們正在考慮事件發生率等等。但我們不會分享點點滴滴的數據，這不是這裡的驅動因素。

Those types of events rates are extremely variable -- subject to a lot of variability and interpretation. If I told you we had a very high event rate, you might say, well, that's because that's great. The placebo event patients are accruing events or you might say, wow, the drug is not working. Or conversely, if we have a low event rate that might indicate that, oh, we don't -- we haven't enrolled the right patients or maybe the drug is working remarkably well. So the primary drivers here are what we understand about science, biology and prior precedent from clinical medicine and clinical trials. And that's the driver.

這些類型的事件發生率變化很大——受到許多變化和解釋的影響。如果我告訴您我們的事件發生率非常高，您可能會說，嗯，那是因為那太好了。安慰劑事件患者正在發生事件，或者您可能會說，哇，藥物不起作用。或者相反，如果我們的事件發生率較低，則可能表明，哦，我們沒有——我們沒有招募合適的患者，或者藥物可能效果非常好。因此，這裡的主要動力是我們對科學、生物學的理解以及臨床醫學和臨床試驗的先例。那就是司機。

Let me just add, Pushkal. I think we will go to stand back a little bit. It's obviously in Alnylam's interest for patients and for everybody concerned to show definitive outcome for vutrisiran. If there had been mass panic at Alnylam, that the study design is wrong or too small or too short, there are many changes we could have made, and we could have made them well in advance.

讓我補充一下，普什卡爾。我想我們會退後一點。顯示 vutrisiran 的明確結果顯然符合 Alnylam 對病人和所有相關人員的利益。如果 Alnylam 出現大規模恐慌，認為研究設計錯誤或太小或太短，我們本可以做出很多改變，我們可以提前做好這些改變。

We have reiterated our confidence over and over again in the study, which as outlined today, deep insights from APOLLO-B, understanding the landscape. And what you see today is a 3-month extension for the last patient giving a reasonable amount of additional data, just further enhance the robustness of what we're going to share with the world come June, July. So I think it's well worth it. It reiterates our confidence in this study.

我們一再重申我們對這項研究的信心，正如今天概述的那樣，這項研究是來自 APOLLO-B 的深刻見解，了解了這一情況。今天您看到的是最後一位患者延長了 3 個月，提供了合理數量的額外數據，進一步增強了我們將在 6 月、7 月與世界分享的內容的穩健性。所以我認為這是非常值得的。它重申了我們對這項研究的信心。

And we haven't fundamentally changed the design to a 1,500 or 2,000 patient study for 5 years. If we were panicked, you would have seen those things some time ago. Others have done what they've done. You've seen what we've done. And on the backdrop of the scientific edifice we've built with the TTR mechanism in APOLLO, in APOLLO-B, I think we should have the confidence.

5 年來我們並沒有從根本上改變 1,500 或 2,000 名患者研究的設計。如果我們驚慌失措，你早就看到那些東西了。其他人已經做了他們所做的事情。你已經看到我們所做的事情了。在我們在APOLLO、APOLLO-B上用TTR機制建立起科學大樓的背景下，我認為我們應該要有信心。

Thanks Akshay, great. Next question?

謝謝阿克謝，太棒了。下一個問題？

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

我們的下一個問題來自高盛的 Salveen Richter。

How much of a differential does extending the duration by 3 months provide instead of conducting the primary analysis at 36 months for all patients? And I'm asking this in the context of recently announced studies in the field that are flexible -- duration up to 48 months or based on events. So just any clarity there? And then secondly, does the monotherapy analysis heighten the need to show significance on all-cause mortality alone just given task on label benefit for frontline use?

與在 36 個月時對所有患者進行初步分析相比，將持續時間延長 3 個月會帶來多少差異？我是在最近宣布的該領域研究的背景下提出這個問題的，這些研究的持續時間長達 48 個月或基於事件。那麼有任何清晰度嗎？其次，單一療法分析是否更需要僅在一線使用標籤效益的任務中顯示全因死亡率的重要性？

Pushkal, are you good to take those?

Pushkal，你願意接受這些嗎？

Yes, absolutely. So Salveen, look, I think what we've done here is we think meaningfully add to the duration of the study or the experience in the study in the tail end. And what we've done is actually for patients who are on the back end of the study, which is where the most -- the greatest events accrue in the placebo arm and where you see the curves diverge, we've added exposure.

是的，一點沒錯。所以薩爾文，我認為我們在這裡所做的是我們認為有意義地增加了研究的持續時間或研究尾部的經驗。我們所做的實際上是針對處於研究後期的患者，也就是安慰劑組中發生最多、最大事件的地方，並且在你看到曲線發散的地方，我們增加了暴露。

It turns out that 60% of patients will actually have additional exposure in the study. And about 1/3 of those, 20% more will actually complete all the way up to 36 months, which is when patients roll over into open-label extension. And so we really -- and we think that, that critical addition, frankly, becomes a no-brainer for us, and it's an important way to further add to study power.

事實證明，60% 的患者實際上會在研究中接受額外的暴露。其中約 1/3（即 20% 以上）實際上會一直完成長達 36 個月，此時患者將進入開放標籤延期。所以我們真的 - 我們認為，坦率地說，這一關鍵的補充對我們來說是理所當然的，這是進一步增強學習能力的重要方式。

So that's why that was done. And again, based on all the trends we've seen in APOLLO-B, which -- where we start to see separation as we've highlighted much, much earlier, we -- it's just -- we think this is a great enhancement that we were able to institute in the study.

這就是這樣做的原因。再說一次，根據我們在 APOLLO-B 中看到的所有趨勢，我們開始看到分離，正如我們之前強調的那樣，我們認為這是一個巨大的增強我們能夠在研究中進行研究。

With regard to your question around monotherapy and all-cause mortality, look, I think it's really important to just remember that in cardiovascular disease, we have about 40 or 50 years of doing outcome studies and they typically focus on MACE type of endpoints, which include death and hospitalization. And the reason that, that's been the focus and accepted by regulators and by the clinical community is because, in general, those events all go hand in hand, hospitalization events, predict mortality and doing mortality alone studies typically are -- tend to be inefficient. They're too large and too long, and we need to get therapies to patients.

關於你關於單一療法和全因死亡率的問題，我認為記住這一點非常重要，在心血管疾病方面，我們進行了大約 40 或 50 年的結果研究，他們通常關注 MACE 類型的終點，這包括死亡和住院。這一直是監管機構和臨床界關注並接受的原因，因為一般來說，這些事件都是齊頭並進的，住院事件、預測死亡率和單獨進行死亡率研究通常效率低下。它們太大太長，我們需要為患者提供治療。

So we've designed a study that is focused on death and hospitalization, and we expect to show a positive result in that study. As well as we will of course, have the breakdown of events under those 2, and we expect them to go in a consistent manner, which is what you would expect to see based on the biology and precedent in almost every other cardiovascular outcomes trial that's been done.

因此，我們設計了一項專注於死亡和住院治療的研究，我們希望在該研究中取得積極的結果。當然，我們也會對這兩項下的事件進行細分，我們希望它們以一致的方式進行，這是您根據生物學和幾乎所有其他心血管結果試驗的先例所期望看到的結果已經完成了。

Our next question comes from the line of Gena Wang from Barclays.

我們的下一個問題來自巴克萊銀行的 Gena Wang。

I have two very quick questions. One is for the 60% monotherapy subgroup. Will your stats analysis or assumption, do you assume most of the tafamidis droppings will be in the placebo arm? And my second question, just wanted to double check my math is correct. And that's based on the Slide 17, you said 60% of the patients remaining on study will have a greater follow-up. 20% more patients will have follow-up to full 36 months. So my calculation will be 40% plus 20% that equals 60% of the patient that will reach for 36 months? Just want to make sure that my math is correct.

我有兩個非常簡短的問題。一種是針對 60% 單一療法亞組。您的統計分析或假設，您是否認為大部分 tafamidis 糞便將出現在安慰劑組中？我的第二個問題，只是想仔細檢查我的數學是否正確。這是基於幻燈片 17，您說 60% 仍在研究的患者將有更大的追蹤。增加 20% 的患者將接受長達 36 個月的追蹤。那麼我的計算是 40% 加 20%，等於 60% 的患者將達到 36 個月？只是想確保我的數學是正確的。

Yes. So Gena, in terms of your questions, the -- as we've said, our TAF drop-in rates are lower than we expected. Obviously, when we designed the study. So we're very encouraged by that. That represents another tailwind that supports the success in the powering of the study. And so I can't get into any more specifics other than that, but to tell you that that's -- we're encouraged by those data.

是的。 Gena，就你的問題而言，正如我們所說，我們的 TAF 下降率低於我們的預期。顯然，當我們設計這項研究時。所以我們對此感到非常鼓舞。這代表了支持該研究成功的另一個動力。因此，除此之外，我無法透露更多細節，但我要告訴你的是——我們對這些數據感到鼓舞。

In terms of the additional follow-up, maybe what I can clarify is those are changes relative to what the study looked like when it was a 30- to 36-month follow-up study. And so what we're seeing is -- and of course, what we're focusing on is patients who remain on study. Throughout the study, we've had patients, for example, who have passed away because of their disease, et cetera. And so what we're saying is that in the patients who remain on study, approximately 60% of them will have some extension of their follow-up in the study and roughly 1/3 of those or 20% additional will get to the full -- the full 36 months. So I hope that clarifies.

就額外的追蹤而言，也許我可以澄清的是，這些變化是相對於 30 至 36 個月的追蹤研究時的情況而言的。所以我們看到的是──當然，我們關注的是仍在接受研究的患者。例如，在整個研究過程中，我們有一些患者因疾病等原因去世。所以我們想說的是，在繼續研究的患者中，大約 60% 的患者將在研究中延長追蹤時間，其中大約 1/3 或額外的 20% 將獲得完整的追蹤——整整36個月。所以我希望能澄清這一點。

Great. Okay. Next question?

偉大的。好的。下一個問題？

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

我們的下一個問題來自 Jefferies 的 Maury Raycroft。

With the new stats plan and the latest conversations with regulators, can you talk more at this point on what the minimum delta and the composite endpoint is that you need to achieve to be stat-sig for monotherapy and combo therapy? And in the top line update, can you commit to reporting when you first hit stat-sig on the separation of the curve, so we get a sense of kinetics versus competitor drugs?

透過新的統計計劃以及與監管機構的最新對話，您現在能否更多地談論單一療法和組合療法需要達到的最小增量和複合終點是多少？在最重要的更新中，您能否承諾在第一次點擊曲線分離上的 stat-sig 時進行報告，以便我們了解與競爭對手藥物相比的動力學？

Yes, Maury, I think what I would say is a couple things. First of all, I think it's widely accepted that death and hospitalization are incredibly clinically relevant endpoints, and there's no sort of minimum threshold there. Obviously, there's always benefit risk. But in general, any benefit in terms of death and hospitalization is considered clinically significant. It is very different than scenarios of looking at NT-proBNP or 6-minute walk test or things like that.

是的，莫里，我想我要說的是幾件事。首先，我認為人們普遍認為死亡和住院治療是與臨床極為相關的終點，並且沒有最低閾值。顯然，利益風險總是存在的。但總的來說，死亡和住院方面的任何益處都被認為具有臨床意義。這與查看 NT-proBNP 或 6 分鐘步行測試或類似測試的場景非常不同。

And as we've said, what we're committing to in the primary -- in the top line results is we will provide p-values on the primary and secondary endpoints, we will provide a statement on safety, and we will make we'll provide information on relevant subgroups, including the TAF subgroup. And of course, we will be providing a lot more data as is our custom, we tend to be quite transparent with our data at scientific and congresses, et cetera, thereafter.

正如我們所說，我們在主要結果中承諾的是，我們將提供主要和次要終點的 p 值，我們將提供安全性聲明，我們將讓我們將提供有關相關分組的信息，包括 TAF 分組。當然，我們將按照我們的慣例提供更多的數據，此後我們往往會在科學和大會等場合對我們的數據保持相當透明。

And as to the kinetics of the effects of either patisiran or vutrisiran for that matter, it's quite clear that the onset is -- appears to be much more rapid than has been seen in other trials with other drugs. So for example, in the original APOLLO with patisiran, by 6 months, you're seeing the separation, post of analyst, but you are seeing a separation in mortality and hospitalization.

至於 patisiran 或 vutrisiran 的作用動力學，很明顯，起效似乎比其他藥物的其他試驗中觀察到的要快得多。例如，在最初的 APOLLO 和 patisiran 中，到 6 個月時，您會看到分析師職位的分離，但您會看到死亡率和住院率的分離。

The same was true in APOLLO-B emerging at 9 months. When you look at recent studies in the ATTR-CM space, it's nothing like that. And my point is that mortality are further attested to by the time separation of (inaudible) 6-minute walk distance or KCCQ, which also promptly occurred within the first few months of the study. So I think not just the magnitude of effect that the kinetics of how our drugs work by depleting the pathogenic protein, which certainly in the peripheral neuropathy study seems to be very potent way to treat the disease will undoubtedly show the impact, I think, ultimately and (inaudible) towards the [climb off].

9 個月大時出現的 APOLLO-B 也是如此。當你查看 ATTR-CM 領域最近的研究時，你會發現事實並非如此。我的觀點是，（聽不清楚）6 分鐘步行距離或 KCCQ 的時間間隔進一步證明了死亡率，這也立即發生在研究的最初幾個月內。因此，我認為，我們的藥物透過消耗致病蛋白發揮作用的動力學，在周邊神經病變研究中無疑是治療該疾病的非常有效的方法，這無疑會最終顯示出影響的大小，我認為，最終以及（聽不清楚）朝向[爬下]。

Our next question comes from the line of Mike Ulz from Morgan Stanley.

我們的下一個問題來自摩根士丹利的 Mike Ulz。

Maybe just one on APOLLO-B. You highlighted the AMVUTTRA monotherapy arm did better than the combination of arm of AMVUTTRA and tafamidis. And I think you highlighted that back at the R&D Day. But just curious, what's the rationale or the mechanism or reason why the combo performs worse than the monotherapy arm?

也許只有阿波羅-B 上的一顆。您強調了 AMVUTTRA 單藥治療組比 AMVUTTRA 和他法米迪聯合治療組的效果更好。我認為您在研發日強調了這一點。但只是好奇，組合療法比單一療法表現更差的基本原理或機製或原因是什麼？

Yes. Mike, maybe just to clarify a couple of points, right? I think first of all, what we are saying is that we -- when we look at the monotherapy data, it's -- you're looking at the effects of -- effect of one drug and certainly comparing that to placebo. And so those placebo patients tend to decline, and it gives the cleanest perspective on the impact that your drug is having, right? And what we've seen out of APOLLO-B, like, was really quite potent substantial effects on the 4 key powered endpoints that we looked at in that study, 6-minute walk test, KCCQ, NT-proBNP and troponin that were sizable and durable.

是的。麥克，也許只是為了澄清幾點，對吧？我認為首先，我們要說的是，當我們查看單一療法數據時，您正在查看一種藥物的效果，並且肯定會將其與安慰劑進行比較。因此，那些安慰劑患者的病情往往會下降，這為您的藥物所產生的影響提供了最清晰的視角，對嗎？我們從 APOLLO-B 中看到的，對我們在該研究中觀察的 4 個關鍵動力終點（6 分鐘步行測試、KCCQ、NT-proBNP 和肌鈣蛋白）確實具有相當強大的實質影響且耐用。

We also saw benefits on mortality as we've been talking about. Some people have brought up some of the data around time to event or -- and the recurrent CV events and I would just point out that, one, it's one endpoint out of all. So I think you'd have to kind of question why that would be the case. And if that makes any clinical or biologic sense.

正如我們一直在談論的那樣，我們也看到了降低死亡率的好處。有些人提出了一些關於事件發生時間或週期性 CV 事件的數據，我只想指出，第一，這是所有端點中的一個。所以我認為你必須質疑為什麼會出現這種情況。如果這有任何臨床或生物學意義的話。

Moreover, when we look at those data, actually, the lack of apparent separation was due to a few early events that happened in the patisiran arm in the first 3 months. And if you look beyond 3 months, in the first 3 months, the drug is just starting to take effect. Beyond 3 months, we actually see good separation even in the monotherapy group, even on outcomes and recurrent CV events specifically. So I think all of that bodes very well. And as it relates to combination. As we've said along, we're very encouraged.

此外，當我們查看這些數據時，實際上，缺乏明顯的分離是由於 patisiran 組在前 3 個月內發生的一些早期事件。如果你觀察 3 個月後的情況，在前 3 個月，藥物才剛開始發揮作用。超過 3 個月後，即使在單一治療組中，我們實際上也看到了良好的分離，甚至在結果和復發性心血管事件方面也是如此。所以我認為所有這些都是好兆頭。因為它涉及組合。正如我們之前所說，我們深受鼓舞。

But certainly, just like you see in blood pressure medicines or other things when you start to combine effective therapeutics together with different mechanisms of action, it can change the magnitude of effect that you might detect but everything that we're seeing coming out of APOLLO B suggest that there will be an effect there, and it's most visibly seen by the outcomes data that we talked about in that study.

但當然，就像你在血壓藥物或其他藥物中看到的那樣，當你開始將有效的治療方法與不同的作用機制結合起來時，它可以改變你可能檢測到的效果的程度，但我們所所看到的一切都來自APOLLO B表明那裡將會產生影響，我們在該研究中討論的結果數據可以最明顯地看出這一點。

Yes, I think we have much larger study with HELIOS-B.

是的，我認為我們對 HELIOS-B 進行了更大規模的研究。

Large and longer study.

大型且長期的研究。

Absolutely.

絕對地。

Yes. And in reference to that large and longer study that is our friend here, been for the patients and physicians ultimately showing a positive outcome. Just before this clinical study, I was looking at the acoramidis space. And if I look at month 18, acoramidis was faring worse than placebo for mortality.

是的。參考我們的朋友那項大型且長期的研究，患者和醫生最終顯示出了積極的結果。就在這項臨床研究之前，我正在研究 acoramidis 空間。如果我觀察第 18 個月，acoramidis 的死亡率比安慰劑更差。

So looking at the wrong time point in a study that's smaller can really lead you (inaudible) so APOLLO-B was highly informative, but it's not surprising that one or two of the endpoints didn't line up where the vast majority did. And ultimately, our friend is the largest, longest study that's ever been conducted and will shortly be completed in ATTR-CM and that's HELIOS-B. So I think getting to over-indexed on one endpoint that went in the wrong direction, you have to be careful about that, can be easily misled.

因此，在規模較小的研究中查看錯誤的時間點確實會導致您（聽不清楚），因此APOLLO-B 的資訊量很大，但其中一兩個終點與絕大多數終點不一致也就不足為奇奇了。最終，我們的朋友是有史以來規模最大、時間最長的研究，並將很快在 ATTR-CM 中完成，這就是 HELIOS-B。因此，我認為在一個方向錯誤的端點上過度索引，你必須小心這一點，很容易被誤導。

Good. I think we've got time for one more question. One last question.

好的。我想我們還有時間再問一個問題。最後一個問題。

Our last question comes from the line of William Pickering from Bernstein.

我們的最後一個問題來自伯恩斯坦的威廉·皮克林。

What is the powering of the study with respect to the overall population at the 0.025 significance level, like I think a lot of the changes make sense, but you've also said in the past that the study is not powered for stat-sig in monotherapy. So if that doesn't hit, are you then in like a more difficult position than you were before the stats plan change?

在 0.025 顯著性水準上，這項研究相對於總體人群的動力是多少，就像我認為很多變化是有意義的，但你過去也說過，這項研究沒有為 stat-sig 提供動力單一療法。那麼，如果這沒有實現，那麼你的處境是否比統計計劃更改之前更困難？

Yes. Well, no, I think what I would take away from today is that the changes we make really we think we've actually enhanced the overall statistical power of the study by adding an extra follow-up for those patients. At the tail end of the study or main study, we think we've added -- we certainly have added statistical power there.

是的。嗯，不，我想我今天要講的是，我們所做的改變確實是我們認為透過為這些患者增加額外的隨訪實際上增強了研究的整體統計能力。在研究或主要研究的結尾，我們認為我們已經添加了——我們當然已經在那裡添加了統計功效。

And the way that we've constructed this endpoint, which again remains focused on the most critical endpoint, which is outcome. We were allowed to -- we were able to look now in the full totality of the population, 660-plus patients in the combination in the overall as well as -- the way I think about it an enriched population of the monotherapy patients, who we expect to be -- have the largest treatment effect and the purest demonstration of what vutrisiran can accomplish in this and do in this disease.

我們建構這個端點的方式仍然關注最關鍵的端點，即結果。我們現在被允許——我們現在能夠觀察整個人群，660 多名患者的組合，以及——我認為單一療法患者的豐富群體，他們我們期望能夠獲得最大的治療效果，並最純粹地展示vutrisiran 在這方面可以取得的成就以及在這種疾病中的作用。

And so we really think we've -- that's really what we've done here. And so we don't think that we've, in any way, made it harder. We think that we've actually made the study better and aligned it where, as Tolga highlighted, where we think the market is going to be for the next several years.

所以我們真的認為我們已經——這確實是我們在這裡所做的。因此，我們認為我們並沒有以任何方式讓事情變得更加困難。正如托爾加所強調的那樣，我們認為我們實際上已經更好地進行了研究，並將其與我們認為未來幾年市場的發展方向進行了調整。

Yes, absolutely. That's great. I think we need to bring the call to a close. I'd like to thank everybody for joining us today. As I said, we're really pleased with the execution. (inaudible) And we're looking closer hitting on our 2024 goals and also becoming a top-tier biotech company. So thank you all, and have a great day.

是的，一點沒錯。那太棒了。我認為我們需要結束通話。我要感謝大家今天加入我們。正如我所說，我們對執行情況非常滿意。 （聽不清楚）我們正在努力實現 2024 年的目標，並成為一家頂級生物技術公司。謝謝大家，祝您有美好的一天。

Thank you. This concludes today conference call. Thank you for participating. You may now disconnect.

謝謝。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。