Alnylam Pharmaceuticals Inc (ALNY) 2024 Q2 法說會逐字稿

Good day and thank you for standing by and welcome to the Alnylam Pharmaceuticals Second Quarter 2024 conference call. (Operator Instructions) I would now like to turn to hand the conference over to the company for their remarks. Please go ahead.

美好的一天，感謝您的耐心等待，歡迎參加 Alnylam Pharmaceuticals 2024 年第二季電話會議。（操作員指示）我現在請公司發言。請繼續。

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

早安.我是 Christine Lindenboom，Alnylam 投資者關係和企業傳播部高級副總裁。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。

For those of you participating via conference call, the accompanying slides can be accessed by going to the Events section of the Investors page of our website investors.alnylam.com/events.

對於透過電話會議參加的人，可以透過造訪我們網站 Investors.alnylam.com/events 的投資者頁面的活動部分來存取隨附的幻燈片。

During today’s call, as outlined in slide 2, Yvonne will offer introductory remarks and provide 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 所示，Yvonne 將發表介紹性言論並提供一般背景資訊。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，然後在我們開始回答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 under the Private Securities Litigation Reform Act of 1995.

我想提醒您，本次電話會議將包含有關 Alnylam 未來期望、計劃和前景的評論，這些評論構成了 1995 年《私人證券訴訟改革法案》中安全港條款的前瞻性陳述。

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

由於各種重要因素，包括我們向美國證券交易委員會提交的最新定期報告中討論的因素，實際結果可能與這些前瞻性陳述所示的結果有重大差異。

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.

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。

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

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. The second quarter of 2024 was a transformative one for Alnylam. Commercially, we achieved a 34% year-over-year growth in global net product revenues, generating $410 million in net product revenues, which was primarily driven by 37% year-over-year growth in our TTR business.

感謝克莉絲汀，感謝大家今天加入電話會議。2024 年第二季對 Alnylam 來說是一個變革性的季度。在商業方面，我們的全球淨產品收入年增了 34%，淨產品收入達到 4.1 億美元，這主要是由我們的 TTR 業務年增 37% 推動的。

And as such, we've raised our revenue guidance for the year by 11% at the midpoint. The commercial capability that we've established over the last five years will continue to drive significant growth for our current business and will be a key to our success as we prepare for a potential launch next year in ATTR cardiomyopathy.

因此，我們將今年的收入指引中位數上調了 11%。我們在過去五年中建立的商業能力將繼續推動我們目前業務的顯著成長，並將成為我們成功的關鍵，因為我們準備好明年可能推出 ATTR 心肌病變。

To that end, the major highlights of Q2 was our announcement of positive top line results from the HELIOS-B Phase 3 study of vutrisiran in ATTR cardiomyopathy, showing that vutrisiran improved cardiovascular outcomes, including a 35% to 36% mortality benefit compared to placebo and demonstrated encouraging safety.

為此，第二季度的主要亮點是我們宣布了vutrisiran 治療ATTR 心肌病變的HELIOS-B 3 期研究的積極頂線結果，表明vutrisiran 改善了心血管結局，包括與安慰劑相比，死亡率降低了35% 至36%並表現出令人鼓舞的安全性。

These results reflect the true power of the RNAi mechanism of action, supporting what we believe to be a highly differentiated therapeutic profile and positioned vutrisiran as the new standard of care in ATTR cardiomyopathy, assuming regulatory approval.

這些結果反映了 RNAi 作用機制的真正力量，支持我們認為高度差異化的治療方案，並將 vutrisiran 定位為 ATTR 心肌病變的新治療標準（假設獲得監管機構批准）。

Moreover, we believe these positive results can establish vutrisiran as an anchor commercial franchise for Alnylam, driving robust top line growth and value creation for many years to come.

此外，我們相信這些積極的成果可以使 vutrisiran 成為 Alnylam 的主要商業特許經營權，從而在未來許多年推動強勁的營收成長和價值創造。

With an eye towards our Alnylam P5x25 goals, we are firm in our belief that we are on track to become 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 of first and/or best-in-class product candidates from our organic product engine, all while delivering exceptional financial results.

著眼於我們的 Alnylam P5x25 目標，我們堅信我們有望成為頂級生物技術公司，在高產產品線的推動下，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來自我們的有機產品引擎一流的和/或一流的候選產品，同時提供卓越的財務表現。

Before I turn it over to Tolga, I'm excited to tell you about the TTR Investor Day that we will be hosting in New York City on Wednesday, October 9th. This event, which will be webcast live, will focus on our leadership in ATTR amyloidosis, including the efforts that we are undertaking to optimize the success of the launch of AMVUTTRA in ATTR cardiomyopathy.

在將其交給 Tolga 之前，我很高興向您介紹我們將於 10 月 9 日星期三在紐約市舉辦的 TTR 投資者日。本次活動將進行網路直播，重點關注我們在 ATTR 澱粉樣變性方面的領導地位，包括我們為優化 AMVUTTRA 在 ATTR 心肌病變中的上市成功所做的努力。

You'll hear from several of my Alnylam colleagues as well as external experts. We'll be sharing more details about this event shortly, and I hope that you can join us in New York on October 9.

您將聽到我的幾位 Alnylam 同事以及外部專家的意見。我們很快就會分享有關此活動的更多詳細信息，希望您能於 10 月 9 日在紐約參加我們的活動。

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

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. Q2 was another strong quarter for our commercial portfolio, delivering net product sales growth of 34% across our portfolio compared with the second quarter of 2023 as we continue to consistently increase the number of patients on therapy in both our TTR and rare franchises.

謝謝伊馮，大家早安。第二季度是我們商業產品組合的另一個強勁季度，與2023 年第二季度相比，我們的產品組合淨銷售額增長了34%，因為我們繼續持續增加TTR 和稀有特許經營中接受治療的患者數量。

Let me now turn to a summary of our second quarter TTR performance. Our TTR franchise achieved $307 million in global net product revenues, representing a 16% increase compared with the first quarter of 2024 and a 37% increase compared with the second quarter of 2023. This strong growth, now approaching six years from our initial commercial launch supports our belief that there remains a significant opportunity in hATTR-PN.

現在讓我總結一下我們第二季的 TTR 表現。我們的 TTR 特許經營業務在全球淨產品收入中實現了 3.07 億美元，較 2024 年第一季成長 16%，較 2023 年第二季成長 37%。從我們最初的商業發佈到現在已經接近六年，這種強勁的成長支持了我們的信念，即 hATTR-PN 仍然存在重大機會。

We are approaching 5,000 patients on treatment with ONPATTRO or AMVUTTRA globally, still a small percentage of the estimated tens of thousands of patients that suffer from this devastating disease.

我們正在全球接近 5,000 名接受 ONPATTRO 或 AMVUTTRA 治療的患者，但僅佔估計數萬名患有這種毀滅性疾病的患者的一小部分。

Now let me provide highlights of our US and rest of world hATTR-PN performance. In the US, combined sales of ONPATTRO and AMVUTTRA increased by 16% compared with the first quarter and by a robust 40% year-over-year as momentum in new patient adds continue to drive strong growth.

現在讓我介紹一下我們美國和世界其他地區的 hATTR-PN 表現的亮點。在美國，ONPATTRO 和 AMVUTTRA 的合併銷售額與第一季相比增長了 16%，由於新患者增加的勢頭繼續推動強勁增長，同比增長了 40%。

The US year-over-year growth was primarily driven by the following. A 34% increase in demand driven by the strength of our ongoing AMVUTTRA patient uptake, more than offsetting the decrease in patients on ONPATTRO that have switched to AMVUTTRA. It is worth noting that at the end of the Q2, approximately 90% of our US TTR are on AMVUTTRA.

美國的年成長主要由以下因素推動。由於我們持續使用 AMVUTTRA 患者，需求增加了 34%，這足以抵消使用 ONPATTRO 的患者轉用 AMVUTTRA 的減少。值得注意的是，在第二季末，我們大約 90% 的美國 TTR 都在 AMVUTTRA 上。

Now, let me turn to our international market, where the TTR franchise growth also increased by 16% compared with the first quarter and 35% year-over-year. The strong year-over-year growth was primarily driven by increased demand for AMVUTTRA as patient uptake remains robust, including from our markets where we successfully launched AMVUTTRA in recent months.

現在，讓我談談我們的國際市場，TTR特許經營成長也比第一季成長了16%，年增了35%。強勁的年成長主要是由於患者對 AMVUTTRA 的需求增加所推動的，其中包括近幾個月我們成功推出 AMVUTTRA 的市場。

Finally, timing of orders in our partner markets, particularly Brazil, also contributed positively to the year-over-year growth. As shared previously, our team is looking forward to bringing vutrisiran to patients with ATTR amyloidosis with cardiomyopathy, assuming successful regulatory review and approval.

最後，我們合作夥伴市場（尤其是巴西）的訂單時機也對年成長做出了積極貢獻。正如之前所分享的，我們的團隊期待將 vutrisiran 用於 ATTR 澱粉樣變性心肌病變患者，前提是獲得成功的監管審查和批准。

We believe we have a tremendous opportunity to transform the treatment paradigm based on the product profile and recent HELIOS-B results, combined with the significant unmet patient needs in ATTR amyloidosis with cardiomyopathy, which is an estimated tenfold larger prevalence than hATTR-PN, where AMVUTTRA is the market leader.

我們相信，根據產品概況和最近的HELIOS-B 結果，再加上ATTR 澱粉樣變性心肌病變患者的顯著未滿足的患者需求，我們有巨大的機會來改變治療模式，據估計，ATTR 澱粉樣變性心肌病變的盛行率比hATTR-PN 高出十倍，其中AMVUTTRA 是市場領導者。

We believe vutrisiran has the potential to address unmet patient needs and become the standard of care treatment of ATTR-CM with a first line and market-leading profile in ATTR-CM, given its unique highly differentiated mechanism of action; enabling rapid knockdown of TTR at the source that is deep and durable; reduction in mortality and CV hospitalization events, as well as substantial impact on measures of disease progression and attractive quarterly dosing schedule with the site of care flexibility and favorable payer dynamics.

我們相信，鑑於 vutrisiran 獨特的高度差異化的作用機制，vutrisiran 有潛力解決未滿足的患者需求，並成為 ATTR-CM 的護理治療標準，在 ATTR-CM 中處於一線和市場領先地位；能夠從深層、持久的源頭快速降低 TTR；死亡率和心血管住院事件的減少，以及對疾病進展指標和有吸引力的季度給藥計劃的重大影響，以及護理靈活性和有利的付款人動態。

We've been deeply committed to advancing treatment options in ATTR amyloidosis and understanding the unique needs of this community over the past decade and have built a strong foundation that will benefit our efforts to address the tremendous potential of ATTR-CM.

過去十年來，我們一直致力於推動 ATTR 澱粉樣變性的治療方案，並了解該社區的獨特需求，並建立了堅實的基礎，這將有利於我們努力發揮 ATTR-CM 的巨大潛力。

At the same time, we recognize the critical importance of scaling our capabilities to establish vutrisiran as a standard of care in ATTR-CM.

同時，我們認識到擴大我們的能力以將 vutrisiran 建立為 ATTR-CM 護理標準的至關重要性。

To this end, we are serially advancing our launch preparation and expanding our capabilities, leveraging our strong foundation, including our deep and credible relations with TTR centers, a global and highly specialized and integrated customer-facing teams that delivers a seamless experience for patients and physicians, our track record of creating strong payer and health system partnerships that supports exceptional patient access, not only in the US, but also across all major global markets, including Canada, Europe and Japan, and our award-winning patient support services team that have enabled us to help patients access their online treatments quickly with one of the fastest timelines in the industry transitioning from start form to therapy and also support patient adherence.

為此，我們正在不斷推進我們的上市準備工作並擴大我們的能力，利用我們強大的基礎，包括我們與TTR 中心的深厚和可信的關係，TTR 中心是一個全球性、高度專業化和整合的面向客戶的團隊，為患者和患者提供無縫的體驗。主要全球市場上支持卓越的患者訪問，以及我們屢獲殊榮的患者支持服務團隊使我們能夠幫助患者以業內最快的時間表之一快速獲得在線治療，從開始形式過渡到治療，並支持患者的依從性。

We're also proud to have established a sustainable rare disease business that addresses a significant unmet patient need. The performance of GIVLAARI and OXLUMO, which delivered [$13 million] in global revenues, combined product sales during the second quarter remains solid as we continue to increase our patient base. The rare disease franchise grew 2% versus the first quarter of 2024 and 25% compared with the second quarter of 2023.

我們也很自豪能夠建立可持續的罕見疾病業務，解決未滿足患者的重大需求。隨著我們繼續擴大患者基礎，GIVLAARI 和 OXLUMO 的業績在第二季度實現了 [1,300 萬美元] 的全球收入和合併產品銷售。罕見疾病特許經營業務較 2024 年第一季成長 2%，較 2023 年第二季成長 25%。

For GIVLAARI, product sales increased by 7% in Q2 compared with the second quarter of 2023, with the following regional highlights. A 17% increase in US, primarily driven by growth in new patients on therapy, an 8% decrease in our rest of world markets, primarily driven by the timing of orders in our partner markets, which offset demand growth across European markets.

對於 GIVLAARI 來說，第二季的產品銷售額較 2023 年第二季成長了 7%，區域亮點如下。美國成長了 17%，主要是由於新接受治療患者的成長推動的；世界其他市場下降了 8%，主要是由於我們合作夥伴市場的訂單時間安排，抵消了整個歐洲市場的需求成長。

For OXLUMO, we delivered a robust 68% year-over-year growth with the following regional dynamics, a 79% increase in the US, primarily driven by demand growth, a 61% growth from our rest of world markets, driven by increased demand in both our European and partner markets.

對於 OXLUMO，我們在以下區域動態下實現了 68% 的強勁同比增長：美國增長了 79%，主要由需求增長推動；世界其他市場增長了 61%，主要由需求增長推動在我們的歐洲和合作夥伴市場。

In conclusion, we delivered strong results in the second quarter and first half of the year with both our TTR and rare franchises, delivering continuous robust growth in patients on therapy and revenue. Accordingly, we're pleased to be upgrading our full year net product revenue guidance today by 11% at the midpoint of our guidance range.

總而言之，我們的 TTR 和稀有特許經營權在第二季和上半年取得了強勁的業績，為患者的治療和收入帶來了持續強勁的成長。因此，我們很高興今天將全年淨產品收入指導上調 11%，達到指導範圍的中點。

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

傑夫稍後將分享更多內容。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？

Thanks, Tolga and good morning, everyone. As Yvonne highlighted in her introduction, the major highlight of the second quarter was our announcement of the exciting and overwhelmingly positive top line results from the HELIOS-B Phase 3 study of vutrisiran in patients with ATTR cardiomyopathy.

謝謝托爾加，大家早安。正如 Yvonne 在介紹中所強調的那樣，第二季度的主要亮點是我們宣布了 vutrisiran 治療 ATTR 心肌病變患者的 HELIOS-B 3 期研究令人興奮且壓倒性積極的頂線結果。

With these results, we now have the first clinical trial data that demonstrate the ability of an RNAi therapeutic to improve cardiovascular outcomes. We observed truly outstanding results in this study with vutrisiran meeting an extraordinarily high bar for efficacy, with statistical significance on all five prespecified primary and secondary endpoints in both of the study population, highlighting the powerful impact of vutrisiran and its mechanism of action on this disease.

有了這些結果，我們現在擁有了第一個臨床試驗數據，證明了 RNAi 療法改善心血管結果的能力。我們在這項研究中觀察到真正出色的結果，vutrisiran 達到了極高的療效標準​​，在研究人群中所有五個預先指定的主要和次要終點均具有統計顯著性，凸顯了vutrisiran 及其作用機制對該疾病的強大影響。

Specifically, we observed 28% and 33% reduction in the risk of all-cause mortality and recurrent CV events in the overall and monotherapy populations, respectively, and 36% and 35% reductions in all-cause mortality in the overall and monotherapy populations respectively.

具體來說，我們觀察到整體和單一治療族群的全因死亡率和復發性心血管事件風險分別降低了28% 和33%，整體和單一治療族群的全因死亡率分別降低了36% 和35 % 。

These outcome benefits were accompanied by clinically significant benefits on six-minute walk test, KCCQ, and NYHA class, all of which are key measures of disease progression. We observed consistent effects in all key subgroups, including patients who are on baseline tafamidis.

這些結果益處伴隨著六分鐘步行測試、KCCQ 和 NYHA 等級的臨床顯著益處，所有這些都是疾病進展的關鍵指標。我們在所有關鍵亞組中觀察到一致的效果，包括基線服用他法米迪的患者。

And finally, vutrisiran demonstrated encouraging safety and tolerability consistent with its established profile. We're announcing this morning that the detailed results from the HELIOS-B study will be presented as a hotline oral presentation at the European Society of Cardiology Congress on Friday, August 30, 2024, in London.

最後，vutrisiran 表現出令人鼓舞的安全性和耐受性，與其既定的概況一致。今天早上我們宣布，HELIOS-B 研究的詳細結果將於 2024 年 8 月 30 日星期五在倫敦舉行的歐洲心臟病學會大會上以熱線口頭報告形式公佈。

We will also host a conference call and webcast during the Congress to discuss these detailed results with investors. We're also hard at work engaging with regulators as we work towards a supplemental NDA filing in the United States in late 2024 with additional global regulatory filings thereafter.

我們還將在大會期間舉辦電話會議和網路廣播，與投資者討論這些詳細結果。我們也努力與監管機構合作，爭取於 2024 年底在美國提交補充 NDA 申請，並隨後在全球範圍內提交更多監管申請。

As a reminder, we will be using our priority review voucher to accelerate the US regulatory review in hopes of bringing this medicine to patients as quickly as possible. In addition to HELIOS-B, we made progress across a number of other pipeline programs, highlighting the breadth of opportunity we have with our RNAi platform.

提醒一下，我們將利用我們的優先審查憑證來加速美國監管審查，希望盡快將這款藥物帶給患者。除了 HELIOS-B 之外，我們還在許多其他管道項目上取得了進展，突顯了我們的 RNAi 平台擁有廣泛的機會。

As we discussed on the last earnings call, we recently reported positive results from our KARDIA-2 Phase 2 study of zilebesiran, showing additive efficacy and good tolerability on top of standard of care antihypertensives in patients with inadequately controlled hypertension.

正如我們在上次財報電話會議上討論的那樣，我們最近報告了zilebesiran 的KARDIA-2 2 期研究的積極結果，顯示出在高血壓控制不充分的患者中，除了標準治療抗高血壓藥物之外，還具有附加療效和良好的耐受性。

KARDIA-3 is now underway, evaluating zilebesiran on top of two or more agents in patients who are at high cardiovascular risk and following that, we look forward to running a cardiovascular outcomes trial, where our goal is to demonstrate the benefits, photonic blood pressure control in patients with high cardiovascular risk by showing reductions in cardiovascular morbidity and mortality.

KARDIA-3 目前正在進行中，在心血管高風險患者中評估齊勒貝西蘭與兩種或多種藥物的結合，隨後，我們期待進行心血管結果試驗，我們的目標是證明光子血壓的益處通過降低心血管發病率和死亡率來控制高心血管風險患者。

We're also excited to have initiated dosing in the Capricorn 1 Phase 2 study of mivelsiran, formerly ALN-APP in patients with cerebral amyloid angiopathy. CAA is the second most common cause of intracerebral hemorrhage and remains highly underdiagnosed with major unmet need.

我們也很高興在 Capricorn 1 2 期研究中開始對 mivelsiran（以前稱為 ALN-APP）治療腦澱粉樣血管病變患者進行給藥。CAA 是腦出血的第二大常見原因，且診斷率仍然很高，需求未被滿足。

We've also advanced ALN-KHK, which is in development for the treatment of type 2 diabetes with initiation of the Part B phase of the Phase 1 study. Our partners continue to make great progress as well. Sanofi submitted regulatory filings for vutrisiran for patients with hemophilia in China, Brazil, and the United States, where the FDA has set a target action date of March 28, 2025.

我們也推進了 ALN-KHK，該藥物正在開髮用於治療第 2 型糖尿病，並已啟動 1 期研究的 B 部分階段。我們的合作夥伴也持續取得巨大進步。賽諾菲在中國、巴西和美國提交了 vutrisiran 用於治療血友病患者的監管文件，FDA 已將目標行動日期定為 2025 年 3 月 28 日。

We've also announced today a pair of updates to our ongoing collaboration with Regeneron. First, we amended the license agreement for cemdisiran, investigational RNA therapeutic in development for the treatment of complement-mediated diseases under which Regeneron gained exclusive rights to the asset as a monotherapy.

今天我們也宣布了與 Regeneron 持續合作的兩項更新。首先，我們修訂了 cemdisiran 的許可協議，cemdisiran 是一種正在開發的研究性 RNA 療法，用於治療補體介導的疾病，根據該協議，再生元獲得了該資產作為單一療法的獨家權利。

In exchange, we received a $10 million upfront payment and are eligible to receive certain regulatory milestones and low double-digit royalties on sales, if approved. Additionally, as part of their regular portfolio review and prioritization efforts, Regeneron has decided to opt out of further co-development and co-commercialization of mivelsiran.

作為交換，我們收到了 1000 萬美元的預付款，如果獲得批准，我們有資格獲得某些監管里程碑和低兩位數的銷售特許權使用費。此外，作為定期投資組合審查和優先排序工作的一部分，再生元已決定選擇退出 mivelsiran 的進一步共同開發和共同商業化。

As such, we now have full global development and commercialization rights to mivelsiran in all indications. We're extremely excited about the potential of this program, our first in the CNS to address the unmet needs of patients in two significant disease areas.

因此，我們現在擁有 mivelsiran 所有適應症的完整全球開發和商業化權利。我們對這個計畫的潛力感到非常興奮，這是我們在中樞神經系統領域的第一個項目，旨在解決兩個重要疾病領域患者未滿足的需求。

CAA, where we've just initiated a Phase 2 study in Alzheimer's disease, where we plan to start a Phase 2 study at or around the end of the year.

CAA，我們剛剛啟動了一項針對阿茲海默症的第二階段研究，我們計劃在今年年底或前後啟動一項第二期研究。

So, in sum, we've made great progress advancing our pipeline and platform with much more to come. As a reminder, we plan to file proprietary IND's for 9 programs by the end of 2025 against targets in the liver, CNS, muscle and adipose.

因此，總而言之，我們在推進我們的管道和平台方面取得了巨大進展，未來還會取得更多進展。提醒一下，我們計劃在 2025 年底前針對肝臟、中樞神經系統、肌肉和脂肪的目標提交 9 個項目的專有 IND。

If we include partnered programs, we anticipate 15 new IND's by the end of 2025, representing a double of our 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 a meaningful impact to patients across multiple disease areas.

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我們的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。

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

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, and good morning everyone. I'm pleased to be presenting a summary of Alnylam's Q2 2024 financial results and discussing our full year guidance. Starting with a summary of our P&L results for Q2 2024 compared with the same period in 2023.

謝謝普什卡爾，大家早安。我很高興介紹 Alnylam 2024 年第二季財務業績摘要並討論我們的全年指導。首先總結 2024 年第二季與 2023 年同期的損益結果。

Total product revenue for the quarter was $410 million or 34% growth versus 2023 with both our TTR and rare franchises reporting strong growth of 37% and 25%, respectively, primarily driven by continued strong demand, as Tolga previously highlighted.

正如Tolga 先前強調的那樣，本季的產品總收入為4.1 億美元，與2023 年相比增長了34%，我們的TTR 和稀有特許經營業務分別實現了37% 和25% 的強勁增長，這主要是由持續強勁的需求所推動的。

Net revenue from collaborations for the quarter was $227 million, representing a $221 million increase when compared with Q2 2023. The increase was primarily driven by the modification of our collaboration agreement with Regeneron resulting in approximately $185 million of revenue, which was previously deferred.

本季合作淨收入為 2.27 億美元，較 2023 年第二季增加 2.21 億美元。這一增長主要是由於我們與 Regeneron 合作協議的修改，導致收入約為 1.85 億美元，此前該收入被推遲。

Royalty revenue for the quarter was $22 million or more than 3 times what was recognized in the second quarter of 2023. The increase was driven by higher Leqvio sales as Novartis continues to grow demand for Leqvio worldwide.

該季度的版稅收入為 2,200 萬美元，是 2023 年第二季確認收入的 3 倍以上。隨著諾華全球對 Leqvio 的需求持續成長，Leqvio 銷售增加推動了這一成長。

Gross margin on product sales was 84% for the quarter compared with 75% in the second quarter of 2023. The improvement in margin is primarily due to higher costs in 2023 associated with canceled manufacturing commitments for ONPATTRO and other adjustments to inventory, for which similar expenses were not realized in 2024.

本季產品銷售毛利率為 84%，而 2023 年第二季為 75%。利潤率的提高主要是由於 2023 年成本上升，原因是取消了 ONPATTRO 的製造承諾以及對庫存的其他調整，而類似的費用在 2024 年並未實現。

I expect our gross margin on product sales will be lower for the balance of the year, driven by higher royalties paid on AMVUTTRA as AMVUTTRA growth continues at a brisk pace.

我預計今年剩餘時間我們的產品銷售毛利率將較低，這是由於 AMVUTTRA 繼續保持快速增長而支付的特許權使用費增加所致。

Our non-GAAP R&D expenses increased 14% in the second quarter compared to the same period in the prior year, primarily due to increased costs associated with our preclinical activities, increased development expenses associated with start-up activities for the zilebesiran and mivelsiran clinical studies and increased employee compensation expenses.

我們第二季的非公認會計準則研發費用與去年同期相比增加了 14%，主要是由於與我們的臨床前活動相關的成本增加、與 zilebesiran 和 mivelsiran 臨床研究啟動活動相關的開發費用增加並增加了員工薪酬支出。

Our non-GAAP SG&A expenses increased 21% in the second quarter compared to the same period in the prior year, primarily due to increased marketing investment associated with promotion of our TTR therapies and increased employee compensation expenses.

我們第二季的非 GAAP SG&A 費用與去年同期相比增加了 21%，這主要是由於與推廣我們的 TTR 療法相關的行銷投資增加以及員工薪資費用增加。

Our non-GAAP operating income for the quarter was $138 million, representing a $292 million improvement compared with Q2 2023, primarily driven by strong top line results, both in product sales as well as revenue from collaborations, as previously highlighted.

我們本季的非GAAP 營業收入為1.38 億美元，與2023 年第二季相比增加了2.92 億美元，這主要是由產品銷售和合作收入方面強勁的營收業績推動的，正如之前強調的那樣。

We ended the second quarter with cash, cash equivalents and marketable securities of $2.6 billion compared with $2.4 billion as of December 31, 2023, with the increase primarily due to increased net product revenues and increased net proceeds from the issuance of common stock in connection with employee stock option exercises.

截至第二季末，我們的現金、現金等價物和有價證券為26 億美元，而截至2023 年12 月31 日為24 億美元，成長主要是由於產品淨收入增加以及與發行普通股相關的淨收益增加員工股票選擇權行使。

We continue to believe our current cash balance is sufficient to bridge us to a self-sustainable financial profile. Now, I'd like to turn to our 2024 guidance where we are updating all components of our full year guidance with the specific details as follows.

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。現在，我想談談我們的 2024 年指南，我們正在更新全年指南的所有組成部分，具體細節如下。

We are increasing our net product revenue guidance from a range of $1.4 billion to $1.5 billion to a range of $1.575 billion to $1.65 billion, representing an 11% increase from the midpoint of the prior to the updated guidance.

我們將產品淨收入指引從 14 億至 15 億美元提高至 15.75 億至 16.5 億美元，較更新指引前的中位數成長 11%。

The primary driver of the increased guidance is the ongoing strength of performance in our hereditary ATTR polyneuropathy franchise. We are increasing our collaboration and royalty revenue guidance from a range of $325 million to $425 million to a range of $575 million to $650 million.

增加指導的主要動力是我們遺傳性 ATTR 多發性神經病變特許經營的持續表現。我們正在將合作和特許權使用費收入指引從 3.25 億美元至 4.25 億美元提高到 5.75 億美元至 6.5 億美元。

The primary driver of the increase is the modification of our collaboration agreement with Regeneron, which resulted in the recognition of approximately $185 million of previously deferred revenue this quarter.

成長的主要驅動力是我們與 Regeneron 合作協議的修改，這導致本季確認了約 1.85 億美元的先前遞延收入。

And lastly, we are increasing our guidance for combined non-GAAP R&D and SG&A expenses from a range of $1.675 billion to $1.775 billion to a range of $1.775 billion to $1.875 billion. There are two primary drivers of the increase.

最後，我們將非 GAAP 研發和 SG&A 支出合併指引從 16.75 億美元至 17.75 億美元提高到 17.75 億美元至 18.75 億美元。成長有兩個主要驅動因素。

First, the opt out of mivelsiran by Regeneron will result in increased R&D investment as the program is now wholly owned by Alnylam. Second, given the strong HELIOS-B top line results, we are increasing our planned ATTR cardiomyopathy launch prep efforts to optimize their preparedness for an early 2025 launch in the US.

首先，再生元選擇退出 mivelsiran 將導致研發投資增加，因為該專案現在由 Alnylam 全資擁有。其次，鑑於 HELIOS-B 的強勁業績，我們正在加大計劃中的 ATTR 心肌病變上市準備工作，以優化其 2025 年初在美國上市的準備工作。

Given the strong momentum in our business underpinning these guidance changes, along with the strength of the HELIOS-B study results and our efforts to prepare for a highly successful ATTR cardiomyopathy launch next year, we are very confident in our ability to achieve both of the Alnylam P5x25 financial goals that we established 3.5 years ago, which include achieving a 40% plus compounded annual growth rate and total revenues across the five-year period and achieving sustainable non-GAAP operating income within the period.

鑑於我們業務的強勁勢頭支撐著這些指導意見的變化，加上 HELIOS-B 研究結果的實力以及我們為明年成功推出 ATTR 心肌病所做的準備，我們對實現這兩個目標的能力非常有信心我們在3.5 年前製定的Alnylam P5x25 財務目標，其中包括在五年期內實現40% 以上的複合年增長率和總收入，並在此期間實現可持續的非GAAP 營業收入。

Let me now turn from financials and discuss some key goals and upcoming milestones slated for mid and late 2024. As was mentioned earlier, we will be presenting detailed results from HELIOS-B at the ESC Congress on Friday, August 30 in London. We will also be hosting a conference call and webcast to discuss the data.

現在讓我從財務問題轉向討論 2024 年中後期的一些關鍵目標和即將到來的里程碑。如前所述，我們將於 8 月 30 日星期五在倫敦舉行的 ESC 大會上展示 HELIOS-B 的詳細結果。我們還將舉辦電話會議和網路廣播來討論這些數據。

We've also announced today that we plan to host a TTR Investor Day on October 9 in New York City. At this event, we will feature senior leaders from Alnylam as well as external experts to highlight the potential of our TTR business. This will be webcast as well.

今天我們也宣布計劃於 10 月 9 日在紐約舉辦 TTR 投資者日。在本次活動中，我們將邀請 Alnylam 的高級領導以及外部專家來強調我們 TTR 業務的潛力。這也將進行網路直播。

We will be submitting a supplemental new drug application for vutrisiran to the FDA using a priority review voucher. We plan to report interim results from Part B of the Phase 1 study of mivelsiran in patients with Alzheimer's disease.

我們將使用優先審查憑證向 FDA 提交 vutrisiran 的補充新藥申請。我們計劃報告 mivelsiran 在阿茲海默症患者中的 1 期研究 B 部分的中期結果。

We expect three trial initiations by the end of 2024, including a Phase 3 study of ALN-TTRsc04 in patients with ATTR cardiomyopathy at or around year-end, a Phase 2 study for mivelsiran in patients with Alzheimer's disease at or around year-end and a Phase 1 study of ALN-BCAT and hepatocellular carcinoma. And we remain on track to file three investigational new drug applications by year-end.

我們預計到 2024 年底將啟動三項試驗，包括年底或年底前後針對 ATTR 心肌病變患者開展的 ALN-TTRsc04 3 期研究、年底左右針對阿茲海默症患者開展的 mivelsiran 2 期研究以及ALN-BCAT和肝細胞癌的1 期研究。我們仍有望在年底前提交三項新藥研究申請。

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

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 will now open the call for your questions.

謝謝你，傑夫。接線員，我們現在將開始電話詢問您的問題。

(Operator Instructions) Ellie Merle, UBS.

（操作員說明）Ellie Merle，UBS。

Hi, this is Jasmine on for Ellie. Thank you so much for taking our question. So, can you discuss the reimbursement landscape in ATTR cardiomyopathy and how you're thinking about the potential difference in pricing between polyneuropathy and cardiomyopathy for AMVUTTRA?

大家好，我是艾莉的茉莉花。非常感謝您提出我們的問題。那麼，您能否討論一下 ATTR 心肌病變的報銷情況以及您如何考慮 AMVUTTRA 多發性神經病變和心肌病變之間定價的潛在差異？

And how could the difference in Medicare Part B versus Part D effect this, especially given some of the IRA changes? Thank you.

Medicare B 部分與 D 部分的差異如何影響這一點，特別是考慮到 IRA 的一些變化？謝謝。

Yes, I think that's the question for Tolga. Maybe just to start off by emphasizing how pleased we are with the commercial performance to date. How peaceful at the commercial performance to date and really see so much opportunity ahead of us, both in polyneuropathy and that is we expand the label to include patients with cardiomyopathy, assuming positive regulatory approval, but Tolga, you may want to respond to the specific questions.

是的，我想這就是托爾加要問的問題。也許首先要強調我們對迄今為止的商業表現有多滿意。迄今為止的商業表現是多麼平靜，我們確實看到了我們面前有這麼多的機會，無論是在多發性神經病方面，還是在假設監管部門獲得積極批准的情況下，我們將標籤擴展到包括心肌病患者，但是托爾加，您可能想對具體的情況做出回應問題。

Yes. Specific to the PN, I think it's actually a testament of the growth that we've been able to deliver this quarter and the prior quarters where patients get on therapy seamlessly. Thanks for our patient support services and preferable position that we have in terms of our access and patients actually stay on therapy.

是的。具體到 PN，我認為這實際上證明了我們在本季和前幾季實現的成長，患者可以無縫接受治療。感謝我們的患者支持服務以及我們在訪問和患者實際繼續治療方面所擁有的更有利的地位。

And that's again, has a lot to do with our profile of the product and quarterly injectables as well as our ability to continue to secure access for those patients. When it comes to CM, we'll be leveraging a similar level of principles, meaning we will obviously make sure that patients have seamless access and they stay on therapy as without the burden of co-pay as little as possible.

這又與我們的產品概況和季度注射劑以及我們繼續確保這些患者獲得藥物的能力有很大關係。在 CM 方面，我們將利用類似程度的原則，這意味著我們顯然將確保患者能夠無縫獲取並繼續接受治療，而無需承擔盡可能少的自付費用。

And given that we are actually physician administered, which allows patients to be on Part B, we believe is going to be a unique advantage in compared to other available or future available products.

鑑於我們實際上是由醫生管理的，這允許患者參加 B 部分，我們相信與其他現有或未來可用的產品相比，這將是一個獨特的優勢。

Thanks Tolga. That's great. Next question please.

謝謝托爾加。那太棒了。請下一個問題。

Thank you. Tazeen Ahmad, Bank of America.

謝謝。塔津·艾哈邁德，美國銀行。

Hi, good morning. Thank you for taking my question. Mine is on vutrisiran and perhaps you can share feedback that you've gotten from physicians about their expectations for use of the product in first line, just based on the top line results from HELIOS-B, which were impressive? It seems clear that there is definitely a market opportunity.

嗨，早安。感謝您回答我的問題。我的藥物是 vutrisiran，也許您可以分享您從醫生那裡得到的有關他們對該產品在一線使用的期望的反饋，僅基於 HELIOS-B 的頂線結果，這些結果令人印象深刻？很明顯，肯定存在市場機會。

I think investors would like to just get a better sense of what portion of that market could end up being first line and what kind of feedback you've gotten from physicians on that question? thanks.

我認為投資者只是想更好地了解該市場的哪一部分最終可能成為一線市場，以及您從醫生那裡得到了關於這個問題的什麼樣的反饋？謝謝。

Yes. And that's a great question. And clearly, there is a unmet medical need here in this disease, which is rapidly progressive and ultimately fatal and we think we have a profile that's absolutely well set up to be standard of care. Tolga?

是的。這是一個很好的問題。顯然，這種疾病的醫療需求尚未得到滿足，這種疾病進展迅速，最終致命，我們認為我們的概況絕對可以成為護理標準。托爾加？

Yes, I mean what we see with the physicians, and we know this from other therapy areas as well. In any progressive debilitating and essentially ultimately fatal disease, it really is imperative to start with the most potent treatment option first. And given the top line HELIOS-B results, we believe atresia is going to be well positioned to be the first time agent.

是的，我的意思是我們從醫生那裡看到的情況，我們也從其他治療領域知道這一點。對於任何進行性衰弱並最終致命的疾病，確實必須先從最有效的治療方案開始。考慮到 HELIOS-B 的頂線結果，我們相信 atresia 將有能力成為首次代理人。

Look, I mean, at the end of the day, HELIOS-B is the most contemporary cardiomyopathy study completed to date and patients had real aggressive backgrounds like around SGL2, tafamidis and yet against this incredibly high bar of contemporary backdrop, we showed a profound impact.

看，我的意思是，歸根結底，HELIOS-B 是迄今為止完成的最現代的心肌病研究，患者俱有真正的攻擊性背景，例如SGL2、tafamidis 周圍的背景，但在當代背景下令人難以置信的高在標準下，我們展示了深刻的影響。

I don't know, Pushkal, if you want to add anything else on this. But I believe this is going to be a key driver in physicians leveraging the first-line treatment.

我不知道，Pushkal，您是否還想對此添加任何其他內容。但我相信這將成為醫生利用第一線治療的關鍵驅動力。

Yes, I think that building to Tolga I totally agree with everything you said and I think, Tazeen, its early days, obviously, but as I think what we've heard repeatedly from clinicians is that they're looking for an orthogonal mechanism of action that can have an impact on this disease.

是的，我認為建立托爾加我完全同意你所說的一切，我認為，Tazeen，顯然還處於早期階段，但我認為我們從臨床醫生那裡反复聽到的是，他們正在尋找一種正交機制可能對該疾病產生影響的行動。

And the investigators and authors for the ESC presentation said that we've shared the data deeply with are incredibly excited. And so we're looking forward to being able to roll those data out. But I think we're seeing a lot of enthusiasm based on the data that we've shared so far.

ESC 簡報的研究人員和作者表示，我們非常興奮地與他們分享了這些數據。因此，我們期待能夠推出這些數據。但我認為，根據我們迄今為止分享的數據，我們看到了很多熱情。

And of course, more to come at ESC, we look forward to that. Next question please.

當然，ESC 還會有更多精彩內容，我們對此充滿期待。請下一個問題。

Thank you. Maury Raycroft, Jefferies.

謝謝。莫里‧雷克羅夫特，傑弗里斯。

Hi. Good morning. Congrats on the quarter. Thanks for taking my question. I'll just -- I'll ask about ESC for the upcoming data. I'm wondering if you'll report KM curves and time to events kinetics for the different mono versus combo subgroups in the study?

你好。早安.恭喜本季。感謝您提出我的問題。我會向 ESC 詢問即將發布的數據。我想知道您是否會報告研究中不同單組與組合組的 KM 曲線和事件動力學時間？

Or maybe talk more about what types of details you plan to disclose at the conference.

或更多討論您計劃在會議上披露哪些類型的細節。

That's a great question, Marin. Clearly, we're working on finalizing the details as we speak. Pushkal?

這是一個很好的問題，馬林。顯然，我們正在努力敲定細節。普什卡爾？

Yes, thanks, Maury. Look, we are working with the investigators and authors to sort of finalize the content. But we plan to go into pretty expansive detail on the end points in the study and the results that we presented at the top line, we think we're really excited to be able to share that now broadly with the community, both the clinical community and the investor community.

是的，謝謝，莫里。看，我們正在與研究人員和作者合作以最終確定內容。但我們計劃對研究的終點和我們在頂線提出的結果進行相當廣泛的細節，我們認為我們真的很高興現在能夠與社區（包括臨床社區）廣泛分享和投資者群體。

So this will include -- I anticipate this will include baseline characteristics. You'll hear about sort of how this is a very contemporary population of patients that was heavily treated with other medications, effective agents. You’ll see the results on the primary endpoint, including the components and all the secondaries.

所以這將包括——我預計這將包括基線特徵。您會聽說這是一個非常現代的患者群體如何接受其他藥物和有效藥物的大量治療。您將看到主要端點的結果，包括元件和所有次要端點。

And we'll also be sharing curves for the primary endpoint and secondary endpoint of all-cause mortality and you'll see that across the key -- you'll see the consistency of effect across a variety of subgroups and specifically, we'll be sharing some curves in the overall and based on baseline tafamidis.

我們還將共享全因死亡率的主要終點和次要終點的曲線，您將看到整個關鍵 - 您將看到各個亞組的效果的一致性，特別是，我們將總體上共享一些曲線並基於基線tafamidis。

So I think you'll get a pretty fulsome view of the results. And of course, we'll have other opportunities to dive deeper into data at HFSA, -- we're limited in how much we can present the ESC and there's a lot of rich data coming out of this incredible clinical trial that we'll be sharing in the weeks to come.

所以我想你會對結果有一個非常滿意的看法。當然，我們還有其他機會在 HFSA 上更深入地研究數據——我們能展示的 ESC 數量有限，而且這項令人難以置信的臨床試驗會產生大量豐富的數據，我們將在未來幾週內分享。

Thanks Pushkal. Next question.

謝謝普什卡爾。下一個問題。

Thank you. Paul Matteis, Stifel.

謝謝。保羅馬蒂斯，斯蒂菲爾。

Hi, thanks so much for taking our question. This is Julian Pino on for Paul. I was just wondering, with respect to the ALN-APP program, can you provide a little bit more color on what the potential Phase 2 design could look like in Alzheimer's and what endpoints you'll be looking at?

您好，非常感謝您提出我們的問題。這是保羅的朱利安·皮諾。我只是想知道，關於 ALN-APP 計劃，您能否提供更多關於阿茲海默症的潛在 2 期設計的情況以及您將關注哪些終點？

And then further, I didn't see anything unless I missed it on the HBM obesity program. Is that still ongoing and curious the status of that as well ?

更進一步，我沒有看到任何東西，除非我錯過了 HBM 肥胖計劃。這是否仍在進行中，並且對它的狀態也感到好奇？

Thank you.

謝謝。

Yes. No. Look, we're delighted with the progress of PLN ACC program, my view answers actually peso. -- ran. It's advancing well, we've been able to demonstrate rapid and robust and sustained reductions in APP, going very well, and we feel there's tremendous potential in the two indications that we are progressing both Alzheimer's disease and cerebral amyloid angiopathy.

是的。不。看，我們對 PLN ACC 計劃的進展感到高興，我的觀點實際上是比索。 ——跑了。它進展順利，我們已經能夠證明 APP 的快速、強勁和持續的減少，進展非常順利，我們認為我們正在進展的阿茲海默症和腦澱粉樣血管病變的兩個跡象具有巨大的潛力。

Pushkal, maybe we're looking at the future.

普什卡爾，也許我們正在展望未來。

Absolutely. So taking your two questions and building over on said with APP, a very exciting program. We just presented some data at AIC actually, that showed that we had consistent knockdown in both soluble APP alpha and beta, but also the downstream disease-related biomarkers of Abeta-40 and [42] that are involved in CAA and Alzheimer's disease and continue to see very encouraging safety coming out of that program as well.

絕對地。因此，回答您的兩個問題，並在 APP 的基礎上進行構建，這是一個非常令人興奮的程序。實際上，我們剛剛在AIC 上展示了一些數據，這表明我們對可溶性APP α 和β 以及與CAA 和阿茲海默症有關的下游疾病相關生物標記Abeta-40 和[42] 進行了一致的敲低，並繼續看到該計劃也帶來了非常令人鼓舞的安全性。

So that program remains on track. We're very excited. As we talked about, we've recently kicked off the study in cerebral amyloid angiopathy like second leading cause of hemorrhage. And as you noted, we will be starting a study in Alzheimer's disease as well.

因此該計劃仍處於正軌。我們非常興奮。正如我們所說，我們最近啟動了腦澱粉樣血管病變的研究，腦澱粉樣血管病變是導致出血的第二大原因。正如您所指出的，我們也將開始一項針對阿茲海默症的研究。

We aren't ready to talk about the specifics of that. We're obviously working through our trial design and -- but we'll share with that with you shortly. But we're very encouraged about this upstream mechanism. Its potential to be very differentiated in this disease space and hopefully have a favorable impact on the disease of Alzheimer's, which I think we all know has a tremendous burden.

我們還沒準備好談論具體細節。顯然，我們正在研究我們的試驗設計——但我們很快就會與您分享。但我們對這種上游機制感到非常鼓舞。它在這一疾病領域具有非常獨特的潛力，並有望對阿茲海默症產生有利的影響，我認為我們都知道阿茲海默症帶來了巨大的負擔。

With regard to your second question on Himani, look, I think -- I don't think there's any really specific updates I want to give on the early preclinical programs other than to say what you heard in the main comments was just we are pushing very aggressively in terms of our 225 strategy to move a multitude of programs forward based on the excitement that we have around the platform here.

關於你關於 Himani 的第二個問題，我想，除了說你在主要評論中聽到的只是我們正在推動的之外，我想對早期臨床前計劃沒有任何真正具體的更新基於我們對這個平台的興奮，我們非常積極地實施225 策略，推動眾多專案向前發展。

And so we are on track for 3-plus IND's this year proprietary IND's by the end of '25 and a doubling of our pipeline by the end of next year. But we'll give updates on those specific programs in due course and then keep you posted.

因此，我們今年預計在 25 年底之前獲得 3 個以上的專有 IND，並在明年年底之前將我們的管道數量增加一倍。但我們會在適當的時候提供這些特定計劃的更新，然後隨時通知您。

Terrific Pushkal, next question.

很棒的普什卡爾，下一個問題。

Konstantinos Biliouris, BMO Capital Markets.

Konstantinos Biliouris，BMO 資本市場。

Good morning. Thanks for taking our questions and congrats on the tremendous progress here. A quick question from us on real world data that recently was published on ATTR polyneuropathy. This study show that a patient under stabilizes progress ONPATTRO very quickly, actually similar rate to national history and then switch to on where the disease progression is almost halting.

早安.感謝您提出我們的問題，並祝賀我們取得的巨大進展。我們就最近發表在 ATTR 多發性神經病變上的現實世界數據提出了一個簡短的問題。這項研究表明，處於 ONPATTRO 狀態下的患者病情進展速度非常快，實際上與國家歷史相似，然後在疾病進展幾乎停止的情況下切換到 O​​NPATTRO。

Any read-through from this study to cardiomyopathy and would you expect similar dynamics with some good years ? Thank you.

從這項研究到心肌病變的任何通讀，您是否期望在一些好的年份有類似的動態？謝謝。

Great question. Pushkal, I think.

很好的問題。普什卡爾，我想。

Yes, thanks, Kostas. I think you were citing a paper that was recently published coming out of a European experience that looked at a cohort of patients who had been on tafamidis and progressed and a proportion of those patients that were put on ONPATTRO and actually seem to have some stabilization of the disease.

是的，謝謝，科斯塔斯。我想你引用的是最近發表的一篇來自歐洲經驗的論文，該論文研究了一組服用 tafamidis 並出現進展的患者，以及一部分服用 ONPATTRO 的患者，實際上似乎病情有所穩定。

These were polyohereditary polyneuropathy patients. Look, I think it's very encouraging. We know that this is a complex disease. Patients do have a progressive do progress with polyneuropathy and with cardiomyopathy.

這些是多重遺傳性多發性神經病變患者。瞧，我認為這非常令人鼓舞。我們知道這是一種複雜的疾病。患者確實患有多發性神經病變和心肌病變。

And so I don't think there's any question that there's an unmet need here for patients to have additional modes of therapy that can address what Tolga highlighted earlier, is a very steadily progressive and fatal disease and so I think we all agree.

因此，我認為毫無疑問，患者對其他治療模式的需求尚未得到滿足，這些治療模式可以解決托爾加之前強調的一種非常穩定進展和致命的疾病，所以我認為我們都同意。

And this is highlighted by the fact that even we have the APOLLO data, APOLLO-B data and we launched an EAP, there was tremendous need for patients who are on stabilizer therapy to get on to an additional orthogonal mechanism of action that stay enrolled very quickly.

即使我們擁有 APOLLO 數據、APOLLO-B 數據並且我們啟動了 EAP，但接受穩定劑治療的患者仍然非常需要採用額外的正交作用機制，從而保持登記狀態，這一事實凸顯了這一點。

So we are very excited about the opportunity where patients need additional therapies and we'll be bringing that forward, we think, now for the CM patients as we have for the PN patients with AMVUTTRA.

因此，我們對患者需要額外治療的機會感到非常興奮，我們認為，我們現在將為 CM 患者提供這一機會，就像我們為接受 AMVUTTRA 的 PN 患者提供的服務一樣。

Great. Next question.

偉大的。下一個問題。

Thank you. Jessica Fye, JPMorgan.

謝謝。潔西卡法耶，摩根大通。

Great. Good morning. Thanks for taking my question. Can you set the stage around the level of detail we should expect with the interim results for Part B as the Phase 1 ALN-APP study later this year? And how we should think about the communication or kind of venue for that update.

偉大的。早安.感謝您提出我的問題。您能否為今年稍後作為 1 期 ALN-APP 研究的 B 部分中期結果的詳細程度做好準備？以及我們應該如何考慮更新的溝通或場所類型。

I'm also curious, would you seek another partner for ALN-APP or do you now plan to keep that wholly-owned? Thank you.

我也很好奇，您會為 ALN-APP 尋找另一個合作夥伴還是您現在計劃保留該公司的全資持股？謝謝。

Well, I'll take the second question first. I mean we're actually delighted to be progressing ALN-APP. As I said, we're very excited about the 2 indications. We've already kicked off our Phase 2 in patients with amyloid angiopathy and planning to start the study in Alzheimer's disease at or around year-end.

嗯，我先回答第二個問題。我的意思是，我們實際上很高興能夠推進 ALN-APP。正如我所說，我們對這兩個跡象感到非常興奮。我們已經啟動了針對澱粉樣血管病變患者的第二階段研究，並計劃在年底或年底左右開始針對阿茲海默症的研究。

So we couldn't be more pleased to have another wholly owned program in our pipeline, and I look forward to moving these programs forward ourselves.

因此，我們非常高興能夠在我們的管道中擁有另一個全資項目，我期待著自己推動這些項目。

Yes. Any other comment -- yes, just to comment on your question, it's a little early to tell you about the specific venue where we'll be talking about the data. But I think what you'll see is starting to see some data with multiple doses in terms of, again, the primary purpose of the study is on safety and pharmacodynamics and so what you'll be seeing is that with multiple dosing.

是的。任何其他評論 - 是的，只是評論你的問題，現在告訴你我們將討論數據的具體地點還為時過早。但我認為您將開始看到一些多次劑量的數據，再次強調，研究的主要目的是安全性和藥效學，因此您將看到的是多次劑量的數據。

But over time, we'll be able to share more and more data coming out of that. But I think, again, our confidence in this program is highlighted by the fact that we've kicked off a study of Phase 2 in CAA, and we'll soon be kicking off a Phase 2 in Alzheimer's disease. So we couldn't -- we're very excited about the potential therapy and continue to investigate it.

但隨著時間的推移，我們將能夠分享越來越多的數據。但我認為，我們已經啟動了 CAA 的第 2 期研究，並且很快就會啟動阿茲海默症的第 2 期研究，這一事實再次凸顯了我們對該計劃的信心。所以我們不能——我們對潛在的療法感到非常興奮，並繼續研究它。

Each potential huge medical knees, we're very, very pleased to be moving forward. Next question.

每個潛在的巨大醫療膝蓋，我們都非常非常高興能夠繼續前進。下一個問題。

Thank you . David Lebowitz, Citi.

謝謝。大衛‧勒博維茨，花旗銀行。

Thank you very much for taking my question. I'm curious, certainly, since Eplontersen has been on the market for a couple of quarters now, have the nature of the discussions with physicians change since the drug's launch at all?

非常感謝您回答我的問題。當然，我很好奇，既然 Eplontersen 已經上市幾個季度了，自從該藥物推出以來，與醫生討論的性質是否發生了變化？

And can you make any commentary on how the market is evolving relative to a new competitive therapy?

您能否對市場相對於新的競爭性療法的發展有何評論？

Great question. Tolga ?

很好的問題。托爾加？

Yes. I mean, as we discussed before, this is a highly devastating disease, and there's still tens of thousands of patients that are expecting to get diagnosed and treated. Therefore, any addition in the market with increased promotional share of voice is a good thing.

是的。我的意思是，正如我們之前討論的，這是一種極具破壞性的疾病，仍有數以萬計的患者期待得到診斷和治療。因此，市場上任何增加促銷份額的舉措都是一件好事。

In respect to the -- how the conversations are shaping up, as you can see from our Q2 results, now this is a two-player market in the US, where we continue to grow very rapidly.

至於對話的進展情況，正如您從我們第二季的業績中看到的那樣，現在這是美國的兩個參與者市場，我們在那裡繼續快速成長。

And I believe the nuances of the products start becoming a lot clearer. As you know, the product profile AMVUTTRA is one that rapidly knocks down the disease-causing protein durably and with a good sustained quarterly injectables.

我相信產品的細微差別開始變得更加清晰。如您所知，產品簡介 AMVUTTRA 是一種能夠快速且持久地消除致病蛋白質的產品，並且具有良好的持續性季度注射效果。

That is becoming a good differentiator. And last but not least, how patients get on the reimbursement and how they stay on the reimbursement. And we're very pleased with the results that we've seen in Q2, and we expect to drive the momentum as such.

這正在成為一個很好的差異化因素。最後但並非最不重要的一點是，患者如何獲得報銷以及如何繼續獲得報銷。我們對第二季的結果非常滿意，我們希望能夠推動這一勢頭。

Excellent. Thank you for taking my question.

出色的。感謝您回答我的問題。

Thank you. Gena Wang, Barclays.

謝謝。王吉娜，巴克萊銀行。

Thank you. I will also ask another question regarding AMVUTTRA . Given this Part B coverage, have you seen any pattern in terms of the patient population regarding -- sorry, the protein from ATTR neuropathy patient regarding patient population and the geographic locations. And quickly on the TTRsc04, any latest thoughts on Phase 3 trial design?

謝謝。我也會問關於 AMVUTTRA 的另一個問題。鑑於 B 部分的報導，您是否看到了有關患者群體的任何模式——抱歉，來自 ATTR 神經病患者的蛋白質與患者群體和地理位置有關。關於 TTRsc04，關於第 3 階段試驗設計的最新想法是什麼？

Yes. Maybe I'll start with the TTRsc04 question. I mean clearly, this is an opportunity to really build a durable franchise in TTR for Alnylam we've seen rapid knockdown, very durable knockdown and we're looking at a program that potentially has improved knockdown with six months of your annual dosing.

是的。也許我會從 TTRsc04 問題開始。我的意思很明確，這是一個真正在TTR 中為Alnylam 建立持久特許經營權的機會，我們已經看到了快速擊倒、非常持久的擊倒，我們正在尋找一個可能通過六個月的年度給藥來改善擊倒的計劃。

So we're really excited about moving forward TTRsc04. So early to comment on the specifics of the clinical program at this point in time, but there will be more to come as we get to the end of this year. Tolga, do you want to take the question on...

因此，我們對推進 TTRsc04 感到非常興奮。目前對臨床計劃的具體細節發表評論還為時過早，但到今年年底，我們將有更多評論。托爾加，你想回答這個問題嗎？

(technical difficulty) [investment]

（技術難度）【投資】

On [reimbursement] yes.

關於[報銷]是的。

So I mean I think one thing is really to keep in mind is we strictly adhere to the patient access philosophy that Alnylam has established over the years. And through that, what we really look at is the co-pay burden on the patients.

因此，我認為真正需要記住的一件事是，我們嚴格遵守 Alnylam 多年來建立的患者就診理念。透過這個，我們真正關注的是患者的共同支付負擔。

Given that our product is reimbursed because it's a physician-administered product through Part B, what we've seen is nearly 70% of our patients remain -- have zero co-pay and up to 80% of patients pay less than $2,000.

鑑於我們的產品是透過 B 部分由醫生管理的產品，因此我們可以報銷，我們看到近 70% 的患者仍然保持零共付額，多達 80% 的患者支付的費用低於 2,000 美元。

This really puts us in an important position where the co-pay burden is quite -- is either less or similar to those products that would be reimbursed in part with the new IRA redesign. So we believe this is a good mix of reimbursement.

這確實使我們處於一個重要的位置，共同支付負擔相當大——與那些透過新的 IRA 重新設計而部分報銷的產品相比，要么更少，要么相似。所以我們相信這是一個很好的報銷組合。

And when it comes to global, we've been able to compete in a very price-sensitive markets across Europe and Japan in polyneuropathy in a very competitive way where we are driving about over 90% market share versus the stabilizer product that's in the market.

就全球而言，我們已經能夠以非常有競爭力的方式在歐洲和日本等對價格非常敏感的多發性神經病市場中進行競爭，與市場上的穩定劑產品相比，我們佔據了約90% 的市場占有率.

Therefore, we really like where we are in terms of our reimbursement policy. And obviously, we're keeping an eye on it to make sure that patients get on this treatment if their physicians decide to do so.

因此，我們非常喜歡我們的報銷政策。顯然，我們正在密切關注，以確保患者在醫生決定的情況下接受這​​種治療。

Thank you. Ritu Baral, TD Cowen.

謝謝。裡圖·巴拉爾，TD·考恩。

Hi, guys. Thanks for taking the question. I wanted to ask to Tolga just how you are now sort of positioning and it sounds like you've been positioning for a while, AMVUTTRA in TTR-CM, -- as far as actual commercial strategies. Jeff mentioned a scale-up of the sales force. Can you talk about the magnitude of that and are you changing the mix of targeting of the sales force?

嗨，大家好。感謝您提出問題。我想問托爾加，你們現在的定位如何，聽起來你們已經定位了一段時間了，AMVUTTRA in TTR-CM，就實際的商業策略而言。傑夫提到了擴大銷售團隊的規模。您能談談這個問題的嚴重程度嗎？

And then in our doc call, our doc calls have mentioned that they do expect despite the wealth of data that this is going to be a commercially sensitive market. How are things like label language, KCCQ, New York Card Association like those are real endpoints in your study.

然後在我們的文檔電話中，我們的文檔電話提到，儘管有大量數據，但他們確實預計這將是一個商業敏感市場。諸如標籤語言、KCCQ、紐約卡協會之類的東西如何成為您研究的真正終點？

How are they going to factor into your marketing message? How important are they? Or is it going to be mortality driven all the way? Thanks.

他們將如何影響您的行銷訊息？它們有多重要？或者它會一直被死亡率驅動嗎？謝謝。

Tolga, straight to you. A terrific question.

托爾加，直接給你。這是一個很棒的問題。

Sure. I mean one thing I just want to make it clear. Obviously, we're going to start off with a very strong foundation where this disease is being treated by multidisciplinary centers and where our organization is there.

當然。我的意思是我只想說清楚一件事。顯然，我們將從一個非常堅實的基礎開始，多學科中心正在治療這種疾病，我們的組織也在那裡。

But when it comes to positioning, I want to make it very clear that we are strictly promoting our polyneuropathy indication, and we will adhere to that until, obviously, we received the label expansion. So I just want to make that clear now.

但說到定位，我想非常明確地表明，我們正在嚴格推廣我們的多發性神經病適應症，並且我們將堅持這一點，直到我們顯然獲得標籤擴展為止。所以我現在只想澄清這一點。

Again, I think, as you highlighted, one of our great advantages is we have deep equities with TTR centers. We've been able to expand our polyneuropathy prescriber base by 50%. We have a well-integrated customer team. Now we highlight the fact that the prevalence of this disease, obviously tenfold.

我再次認為，正如您所強調的，我們的一大優勢是我們與 TTR 中心擁有深厚的股權。我們已經能夠將多發性神經病變處方者基礎擴大 50%。我們擁有一支高度整合的客戶團隊。現在我們強調一個事實，這種疾病的盛行率顯然是原來的十倍。

So I just want to make that clear now again, I think as you highlighted, one of our great advantages is we have deep experience with TTR centers. We've been able to expand our polyneuropathy prescriber base by 50%. We have a well-integrated customer team.

所以我現在想再次澄清這一點，我認為正如您所強調的，我們的一大優勢是我們在 TTR 中心方面擁有豐富的經驗。我們已經能夠將多發性神經病變處方者基礎擴大 50%。我們擁有一支高度整合的客戶團隊。

Now we highlight the fact that, you know, the prevalence of this disease obviously tenfold. Having said that, the number of prescribers is not tenfold. It's a lesser magnitude of prescriber base. Therefore, we believe we can actually scale this up in the appropriate way.

現在我們強調一個事實，你知道，這種疾病的盛行率顯然是原來的十倍。話雖如此，開處方的人數不到十倍。處方者基礎的規模較小。因此，我們相信我們實際上可以以適當的方式擴大規模。

And then when it comes to in rare diseases, having an integrated customer-facing team where you have good coverage of reimbursement support, you have good coverage of medical and field organization support is going to be key, we have that.

然後，當涉及到罕見疾病時，擁有一個面向客戶的綜合團隊，在其中獲得良好的報銷支持，獲得良好的醫療和現場組織支持將是關鍵，我們擁有這些。

And the last piece, I think, of the puzzle is a very good, strong established patient support services, where we are actually quite pleased with the time to treatment from patient start forms into patients getting reimbursed and starting on therapy. Now those are obviously some of the capabilities where we're keeping an eye on, and we're going to scale that out.

我認為，這個難題的最後一部分是非常好的、強大的患者支援服務，我們實際上對從患者開始表格到患者得到報銷並開始治療的治療時間感到非常滿意。現在，這些顯然是我們正在關注的一些功能，我們將擴大其規模。

Now when it comes to your second part of your question, in terms of labelling, how we're going to be positioning the product, obviously, that's going to be depending on the FDA and where we don't comment given the label discussion that we have.

現在，當談到您問題的第二部分時，就標籤而言，我們將如何定位產品，顯然，這將取決於 FDA，鑑於標籤討論，我們不會發表評論我們有。

I think what you will see at ESC is going to give you further color about the robustness of this data and how we can actually be able to communicate effectively both primary composite and secondary end points as well as the oral cost mortality. We believe there's going to be a clear differentiation for our products.

我認為您將在 ESC 看到的內容將使您進一步了解這些數據的穩健性，以及我們如何能夠有效地溝通主要複合終點和次要終點以及口服成本死亡率。我們相信我們的產品將會有明顯的差異化。

And last but not least is the product profile itself. I mean the -- given that this is a swiftly progressing reversible disease to be able to demonstrate a rapid knockdown that really knocks on the disease closing pathogen as quickly as possible is going to be important.

最後但並非最不重要的是產品簡介本身。我的意思是——考慮到這是一種快速進展的可逆疾病，能夠證明快速擊倒，真正盡快擊倒疾病封閉病原體將是很重要的。

Given the convenience of quarterly dosing is going to be important, given that how patients actually quickly get on access to this treatment is going to be very critical. So combining all this with the data that we have with HELIOS-B and the product profile, we really do strongly believe physicians will choose AMVUTTRA, if approved as a first-line product given where the disease is, given what the product is and given where we have the data.

鑑於每季給藥的便利性將非常重要，考慮到患者如何真正快速獲得這種治療將非常關鍵。因此，將所有這些與我們在 HELIOS-B 上獲得的數據和產品概況相結合，我們確實堅信，如果根據疾病所在、產品性質和給予情況批准作為一線產品，醫生會選擇 AMVUTTRA我們有數據的地方。

Thanks, Tolga. Next question.

謝謝，托爾加。下一個問題。

Salveen Richter, Goldman Sachs.

薩爾文·里克特，高盛。

Hi. Thanks for taking my question and congrats on the results. This is Tom on for Salveen. Just a question on your discussions with KOLs and cardiologists. Have you heard a number or range for the additive benefit on top of TA that would be considered meaningful in DC?

你好。感謝您提出我的問題並祝賀結果。這是薩爾文的湯姆。只要問一下您與 KOL 和心臟科醫生討論的問題。您是否聽說過 TA 以外的附加收益的數字或範圍在 DC 中被認為是有意義的？

And just a follow-up on the commercial questions. Over the longer term, what's your strategy here for growing the market beyond taking share or adding on top of tafamidis? Thank you so much.

這只是商業問題的後續行動。從長遠來看，除了搶佔市場份額或在 tafamidis 基礎上增加產品之外，你們的市場成長策略是什麼？太感謝了。

Yes. So maybe I can take the first part of your question in terms of is there some numerical target in terms of benefit on top of tafamidis. I think really, what I would say is the feedback that we've gotten all along, and I think has only been accentuated since we've shared the top line results with KOLs is just the enthusiasm for a new medicine to help these patients, first and foremost.

是的。因此，也許我可以回答你問題的第一部分，即在 tafamidis 的益處方面是否存在一些數字目標。我真的認為，我想說的是我們一直以來得到的反饋，而且我認為自從我們與 KOL 分享了最重要的結果後，反饋就更加突出了，那就是對幫助這些患者的新藥的熱情，首先也是最重要的。

Second of all, what they're seeing from the top line results is an opportunity for this drug to actually access the broad spectrum of patients with this disease. We saw strong efficacy as a monotherapy across all the endpoints.

其次，他們從最重要的結果中看到的是，這種藥物有機會真正接觸到廣泛的患有這種疾病的患者。我們看到作為單一療法在所有終點上都有很強的療效。

But we saw equally strong efficacy in the overall population, which I'll remind you includes 40% of patients who start on background tap and a good proportion of people who actually add an on TAP and added on SGLT2 inhibitors had diuretic intensification.

但我們在整體人群中看到了同樣強大的療效，我要提醒您的是，其中包括40% 開始使用背景Tap 的患者，以及實際添加TAP 和SGLT2 抑製劑的很大比例的患者，這些患者都進行了利尿強化。

And so -- and I think as some have noticed from the top line results -- there is -- if you just look at the mortality numbers, the strength of the data in the overall population, both in terms of the actual magnitude of effect as well as the p-value was somewhat stronger, which implies a pretty substantial effect in the add-on population.

因此，我認為正如一些人從頂線結果中註意到的那樣，如果你只看死亡率數字，總體人口中數據的強度，無論是從實際影響程度來看，還是有的並且p 值稍強，這意味著對附加人群有相當大的影響。

Now that's encouraging because it wasn't powered or designed to show an effect in that population. But to see what we're seeing is consistent evidence of additive efficacy, I think, is encouraging. So there's no numerical target, but I think what people are seeing is a picture of a drug that's emerging to them that looks quite -- to be quite effective for this disease.

現在這是令人鼓舞的，因為它的動力或設計並不是為了在該人群中顯示效果。但我認為，看到我們所看到的一致的累加功效證據是令人鼓舞的。所以沒有數字目標，但我認為人們看到的是一種正在出現的藥物的圖片，看起來對這種疾病非常有效。

I think Tolga add a few words about the market. We've talked about how we think about the market pre-tax loss of exclusivity and post-tax loss of exclusivity. Perhaps you could make a few comments on.

我認為托爾加補充了一些關於市場的內容。我們已經討論瞭如何看待市場稅前排他性損失和稅後排他性損失。也許你可以發表一些評論。

Yes, I mean, thinking of that.

是的，我的意思是，想到這一點。

We believe, given that this is an area of disease, it's unusual for a combination therapy to be used given some of the access challenges. However, I think we believe given the data set, we believe there's going to be some combination use early on prior to the TAF exclusivity.

我們認為，鑑於這是一個疾病領域，考慮到一些准入挑戰，使用聯合療法是不尋常的。然而，我認為我們相信鑑於數據集，我們相信在 TAF 獨佔權之前早期將會有一些組合使用。

But to your point, what's really important is the category growth. What we've seen is given that the diagnostic tools have advanced over the last six years, there's easy access to -- for patients to get diagnosed early.

但就您而言，真正重要的是品類成長。我們所看到的是，鑑於診斷工具在過去六年中取得了進步，患者可以輕鬆獲得早期診斷。

I think having increased share of voice and promotional awareness of this category is going to help. The only available treatment has actually done a phenomenal job of expanding the diagnosis rates. And with added voices in this category is only going to accelerate the treat diagnosis and treatment rates. And we believe those patients deserve many options to be treated to.

我認為增加這一類別的發言權和宣傳意識將會有所幫助。唯一可用的治療方法實際上在提高診斷率方面取得了驚人的成果。隨著這一類別的聲音的增加，只會加快治療診斷和治療的速度。我們相信這些患者應該有多種治療選擇。

Jeff, anything you want to add?

傑夫，你還有什麼要補充的嗎？

I don't have anything further.

我沒有更多的事情了。

Great. Thank you. Thanks, Tolga.

偉大的。謝謝。謝謝，托爾加。

Thank you. MIke Ulz, Morgan Stanley.

謝謝。麥克烏爾茲，摩根士丹利。

Good morning. Thanks for taking the question and congrats on the quarter as well. Maybe just a quick follow-up on some prior questions in terms of the market opportunity for TTR CM. Can you just talk a little bit about why 80% of patients go untreated currently.

早安.感謝您提出問題，也恭喜本季。也許只是對之前有關 TTR CM 市場機會的一些問題進行快速跟進。能簡單談談為什麼目前80%的患者無法接受治療嗎？

It sounds like diagnosis is probably one of the key factors, but what are some of the other factors? And then how do you reduce that going forward? Thanks.

聽起來診斷可能是關鍵因素之一，但其他因素是什麼？那麼接下來該如何減少這種情況呢？謝謝。

I think another one for you.

我想再給你一份。

Yes. Look, this is a disease, especially in the wild-type cardiomyopathy. Patients don't start having these symptoms until sometimes it's too late. So that's one of the key drivers. The second thing is there are only a few multi-suite centers.

是的。看，這是一種病，尤其是野生型心肌病變。患者直到有時為時已晚才開始出現這些症狀。這是關鍵驅動因素之一。第二件事是只有少數多套房中心。

What we've seen is those multidiscipline centers start more expanding more and the awareness of how the disease actually manifests itself is being picked up by authorities as well as much as we say, it's tenfold of the polyneuropathy, it's still a rare disease.

我們所看到的是，那些多學科中心開始擴大規模，當局也開始意識到這種疾病的實際表現，正如我們所說，它是多發性神經病變的十倍，它仍然是一種罕見的疾病。

In the US, it's less than 200,000 patients. Therefore, it is not as common as what doctors used to seeing, cardiologists or neurologists or even in some cases, orthopedic surgeons where they see bilateral carpal tea syndrome or spinal stenosis.

在美國，患者數量不到 20 萬。因此，它並不像以前醫生、心臟科醫生或神經科醫生，甚至在某些情況下，骨科醫生看到的雙側腕茶綜合症或椎管狹窄那麼常見。

It's an area where needs more education, more disease awareness. And we believe having more voices articulating how disease manifests itself and help the patients to get treated early is going to be key. One of the things we're doing, and I believe others will be doing as well is to engage with a lot of centers to make sure that on electronic medical records, patients get start flagged early.

這是一個需要更多教育和更多疾病意識的領域。我們相信，讓更多的聲音闡明疾病的表現並幫助患者儘早接受治療將是關鍵。我們正在做的事情之一，我相信其他人也會做，就是與許多中心合作，以確保在電子病歷上，患者儘早開始標記。

I think these are some of the initiatives that the industry is going to be making to make sure those patients get quickly flagged. I don't know, Pushkal, do you have anything?

我認為這些是該行業將採取的一些舉措，以確保這些患者得到快速標記。我不知道，普什卡爾，你有什麼嗎？

Yes. No, Tolga, you said it very well. I mean I think the only thing I would just add it. Just a reminder that until five years ago, there was no therapy for these patients at all that was specific, right? And so they were treated as sort of (technical difficulty) an ejection fraction.

是的。不，托爾加，你說得很好。我的意思是我認為我唯一會添加它。只是提醒一下，直到五年前，還沒有針對這些患者的特異性治療方法，對嗎？因此，它們被視為某種（技術難度）射血分數。

And I think to point now, we have a therapy, hopefully, assume multiple therapies for these patients. We've now over just the last few years had the proliferation of noninvasive diagnostic methods to identify these patients.

我想現在要指出的是，我們有一種療法，希望能為這些患者提供多種療法。在過去的幾年裡，我們已經有了大量的非侵入性診斷方法來識別這些患者。

And we're starting to understand more where how to identify these patients based on red flag symptoms such as polyneuropathy or spinal stenosis or carpal tunnel syndrome, things like that. So I think there is just a heavy need for more disease education awareness because we now have, we believe, hopefully, multiple therapies for these patients that can actually stem the progression of this result to otherwise progressive in fatal disease.

我們開始更多地了解如何根據多發性神經病變、椎管狹窄或腕管綜合症等危險信號症狀來識別這些患者。因此，我認為迫切需要更多的疾病教育意識，因為我們相信，我們現在有希望為這些患者提供多種治療方法，這些治療方法實際上可以阻止這種結果發展為致命疾病。

So I think there is a lot of growth here in terms of patients to treat.

所以我認為在需要治療的患者方面有很大的成長。

Helpful, thank you.

有幫助，謝謝。

Thank you. William Pickering, Bernstein.

謝謝。威廉‧皮克林，伯恩斯坦。

Yes. Thank you so much for taking my question and congrats on the great results. Looking ahead to ESC, there seems to be a lot of investor interest in comparing the vutri monotherapy arm with the TAF plus placebo arm.

是的。非常感謝您提出我的問題，並祝賀取得的優異成績。展望 ESC，似乎有很多投資者有興趣比較 vutri 單藥治療組與 TAF 加安慰劑組。

Could you talk about the extent to which you think that is a helpful comparison and any limitations relative to just looking at Q3 versus placebo and the background TAF?

您能否談談您認為這種比較在多大程度上是有用的，以及相對於僅查看 Q3 與安慰劑和背景 TAF 的任何限制？

Thank you.

謝謝。

Yes. Thanks, Will. Look, I think what we have here with USB is really a very, very rich study, right? This was a study done 655 patients in the modern era. These were patients who were diagnosed with noninvasive means. As we've talked about, and we'll share more at ESC, it was a pretty rigorous test.

是的。謝謝，威爾。看，我認為我們對 USB 的研究確實非常非常豐富，對嗎？這是一項針對現代 655 名患者進行的研究。這些患者是透過非侵入性手段診斷出來的。正如我們所討論的，並且我們將在 ESC 分享更多內容，這是相當嚴格的測試。

These are patients, 40% who are already on an effective therapy, a good proportion of the monotherapy arm. We started another effective therapy in the midst of the study, patients started SGLT2s, other things. So it was a pretty rigorous test and the results we believe are very, very encouraging.

這些患者中，40% 已接受有效治療，在單一治療組中佔很大比例。我們在研究期間開始了另一種有效的治療，患者開始使用 SGLT2，等等。所以這是一次非常嚴格的測試，我們相信結果非常非常令人鼓舞。

The one thing the study was not was a head-to-head study with tafamidis. That is the one thing it was not. It was not designed for that purpose. And so the comparison that you're referring to really is a nonrandomized comparison. And as you can imagine, the patients who entered in on TAF were different because they've been on the drug for a while.

這項研究不是與 tafamidis 進行頭對頭研究。這是唯一一件事不是。它不是為此目的而設計的。因此，您所指的比較實際上是非隨機比較。正如您可以想像的那樣，接受 TAF 治療的患者有所不同，因為他們已經服用該藥物一段時間了。

Obviously, there were geographic differences in those patients. The minority of the TAF patients came from the US. So comparing that then to the vutri patients who are on monotherapy, it's really unfortunately a flawed analysis.

顯然，這些患者存在地域差異。少數 TAF 患者來自美國。因此，與接受單一療法的 vutri 患者相比，不幸的是，這是一個有缺陷的分析。

I think what we'll see, as we highlighted in the top line results is that vutri appears to have really encouraging efficacy on every parameter we measured both as a monotherapy and evidence of additive efficacy on top of tafamidis and consistent results across the whole series of endpoints that we've looked at.

我認為我們將看到，正如我們在頂線結果中所強調的那樣，vutri 似乎對我們作為單一療法測量的每個參數都具有令人鼓舞的功效，並且在tafamidis 之上具有附加功效的證據以及整個系列的一致結果我們已經研究過的端點。

Next question.

下一個問題。

Thank you. Myles Minter, William Blair.

謝謝。邁爾斯·明特，威廉·布萊爾。

Hi, thanks for taking the question. Just with as releasing that draft guidance on TCICM pricing. I know that was in relevance to tafamidis, but there's also some commentary about vutrisiran in that as well. Is Alnylam intending to be at that public hearing in September '20?

您好，感謝您提出問題。正如發布 TCICM 定價指南草案一樣。我知道這與 ​​tafamidis 有關，但其中也有一些關於 vutrisiran 的評論。Alnylam 是否打算參加 20 年 9 月的公開聽證會？

And if you are, are you going to be presenting something on cost effectiveness of future (technical difficulty) Thanks very much.

如果是的話，您是否會介紹一些有關未來成本效益（技術難度）的內容，非常感謝。

Yes. Thank you for that question. As ISI think, noted, they made this assessment prior to our disclosure of HELIOS-B top line results, and therefore, it was in a complete analysis. We remain engaged with any health outcomes authority, and we'll continue to engage with ISE and others. We haven't disclosed whether we would be part of the hearing.

是的。謝謝你提出這個問題。正如 ISI 所認為的那樣，他們在我們披露 HELIOS-B 頂線結果之前就做出了這項評估，因此，這是一次完整的分析。我們將繼續與任何健康結果權威機構合作，並將繼續與 ISE 和其他機構合作。我們尚未透露是否會參加聽證會。

Okay. I think we have time for one more question. Last question please.

好的。我想我們還有時間再問一個問題。最後一個問題請。

Luca Issi, RBC Capital.

盧卡·伊西，加拿大皇家銀行資本。

Oh great. Thanks so much for squeezing me in and congrats on all the progress. Maybe circling back on Gena's question here Pushkal, for TTR S4 which is obviously super important as we think about the royalty to Sanofi on the Phase 3.

哦，太棒了。非常感謝您對我的鼓勵，並祝賀我所取得的所有進展。也許回到 Gena 的問題 Pushkal，對於 TTR S4，這顯然非常重要，因為我們考慮到賽諾菲在第 3 階段的特許權使用費。

Do you basically need to run another HELIOS speed or you can maybe get away with a smaller PK/PD trial? And maybe related, what's the dose that you're going to pursue? I think the sad portion of the trial, you went all the way to 600 milligrams. So just wondering if that is the go-forward dose.

您基本上需要運行另一個 HELIOS 速度，或者您可以進行較小的 PK/PD 試驗？也許相關的是，您要服用的劑量是多少？我認為試驗中最令人悲傷的部分是，您一路服用了 600 毫克。所以只是想知道這是否是前進劑量。

Thanks so much.

非常感謝。

Okay. Well, we're going to come back to that question because as I said, we're not ready really to get into the details of what the next detailed steps in our clinical plans. So we'll come back and share more on that later, but thanks for your interest. We're also very excited about the program. Thanks, Luca.

好的。好吧，我們將回到這個問題，因為正如我所說，我們還沒有真正準備好詳細了解我們臨床計劃中下一步的詳細步驟。因此，我們稍後會回來分享更多內容，但感謝您的關注。我們也對該計劃感到非常興奮。謝謝，盧卡。

Okay. I think that brings our call to a close. And I just want to thank everybody for joining. I mean really the second quarter of 2024 has marked an inflection point in our items journey and we really are proud of our progress.

好的。我認為我們的通話就此結束。我只想感謝大家的加入。我的意思是，2024 年第二季確實標誌著我們產品之旅的轉折點，我們真的為我們的進步感到自豪。

As Tolga described, the being robust commercial growth. Pushkal's gone through some of the incredible advancements in our pipeline and now more than ever, we believe that we're firmly on a path to becoming a top-tier biotech company. So thank you, everybody, and have a great day.

正如托爾加所描述的，商業成長強勁。Pushkal 在我們的產品線中經歷了一些令人難以置信的進步，現在我們比以往任何時候都更相信我們堅定地走在成為頂級生物技術公司的道路上。謝謝大家，祝您有美好的一天。

Thank you. This does conclude today's program. Thank you for your participation. You may disconnect at any time.

謝謝。今天的節目到此結束。感謝您的參與。您可以隨時斷開連線。