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美國
證券交易委員會
華盛頓特區20549
____________________________________________
表格 10-Q
____________________________________________
根據1934年證券交易法第13或15(d)節的季度報告
截至季度結束日期的財務報告2024年9月30日
或者
根據1934年證券交易法第13或15(d)節的轉型報告書
過渡期從___________到_____________
委員會文件號 001-36407
__________________________________________
ALNYLAm製藥公司。
(按其章程規定的確切註冊人名稱)
__________________________________________
特拉華州
(註冊或組織的)提起訴訟的州或其他司法管轄區(如適用)
組建國的駐地
77-0602661
(IRS僱主
唯一識別號碼)
675 West Kendall Street,
Henri A. Termeer Square
劍橋, 馬薩諸塞州
(主要領導機構的地址)
02142
(郵政編碼)
(617) 551-8200
(註冊人電話號碼,包括區號)
__________________________________________
每個交易所的名稱
每種類別的證券交易標誌名稱爲每個註冊的交易所:
普通股,每股面值$0.01ALNY納斯達克證券交易所 LLC
選擇√標記,指出註冊者(1)在過去的12個月內(或註冊者需要提交此類報告的較短期間內),是否已提交證券交易法1934年第13條或15(d)條要求提交的所有報告;以及(2)在過去的90天內是否已受制定規定的報告提交要求的約束。  x沒有 ☐
請表明,註冊人在過去12個月(或註冊人需要提交此類文件的更短期間)在規章S-t(本章第232.405節)第405條規定下提交了每個交互式數據文件。     x 不 ☐
請在交易所法規則120.2規定的「大型加速申報人」、「加速申報人」、「小型報告公司」和「新興成長公司」的定義中選中相應選項。

大型加速報告人x加速文件申報人
非加速文件提交人更小的報告公司
新興成長公司
如果是新興成長公司,請在複覈者處標明勾選符號,說明註冊者是否選擇不使用依據證券交易法第13(a)條規定提供的任何新的或修訂後的財務會計準則的擴展過渡期。 ☐
請以勾選方式表明報名者是否爲外殼公司(如《交易所法》第120億.2條中所定義)。是x
2024年10月25日,註冊人擁有 128,980,917 股普通股,每股面值0.01美元。



ALNYLAm製藥公司。
第10-Q表格季度報告

目錄
頁碼
編號

「安樂沃」,ONPATTRO®,AMVUTTRA®,GIVLAARI®,OXLUMO®IKARIA™ 是 Alnylam Pharmaceuticals, Inc. 的商標和註冊商標。我們的標誌、商標和服務標誌是 Alnylam 的財產。在這份第 10-Q 表格的季度報告中出現的所有其他商標或服務標誌都歸其各自持有人所有。
2

目錄
關於前瞻性陳述的注意事項
本季度10-Q表格中包含根據1933年證券法第27A條修訂案和1934年證券交易法第21E條修訂案屬於前瞻性陳述。我們打算使這些前瞻性陳述受到1995年《私人證券訴訟改革法》中關於前瞻性陳述的安全港規定的保護,幷包括本聲明以遵守這些安全港規定。本季度10-Q表格中包含的除歷史事實陳述之外的所有聲明均爲前瞻性陳述。在某些情況下,您可以通過術語識別前瞻性陳述,例如「可能」,「將」,「應該」,「可能」,「預期」,「計劃」,「意圖」,「預期」,「相信」,「估計」,「預測」,「潛在」,「繼續」,或這些術語的否定形式或其他類似術語。這些前瞻性陳述包括但不限於以下聲明:
我們對已獲批准和研究中的RNAi治療潛力持肯定態度,包括ONPATTRO、AMVUTTRA、GIVLAARI、OXLUMO、Leqvio®(inclisiran)、fitusiran和zilebesiran;
我們計劃進行更多全球監管申請,並持續推出ONPATTRO、AMVUTTRA、GIVLAARI、OXLUMO產品,以及我們合作伙伴關於Leqvio和fitusiran的計劃;
我們獲得AMVUTTRA(vutrisiran)用於治療伴有心肌病的ATTR澱粉樣變性的監管批准能力;
我們對ONPATTRO,AMVUTTRA,GIVLAARI,OXLUMO,Leqvio,fitusiran或任何未來產品的市場規模潛力和成功商業化的期望;
我們獲取和維持ONPATTRO、AMVUTTRA、GIVLAARI、OXLUMO或任何未來產品的監管批准和定價和報銷能力,以及我們合作伙伴對Leqvio和fitusiran相關方面的能力;
我們研究和開發項目的進展情況,包括罕見病和常見病領域的項目;
通過我們的新技術,包括IKARIA平台,以及將我們的產品引擎擴展至額外肝外組織,有望產生改進的產品特性。
我們目前和預期臨床試驗,並期望關於這些試驗的數據報告。
監管申報時間和與監管機構的互動、行動或建議可能會影響臨床試驗的設計、啓動、時間、持續性和/或進展,或導致需要額外的臨床前和/或臨床測試或監管批准的時間或可能性;
我們製造業-半導體的運營狀況,以及由我們或他們的代工廠商或由我們或我們的合作方製造和供應ONPATTRO、AMVUTTRA、GIVLAARI、OXLUMO或任何由我們或我們的合作方開發和商業化的產品候選者(或其他產品或由我們或合作方開發和商業化的產品候選者)的延遲、中斷或失敗情況;
未來任何大流行病或公共衛生緊急事件對我們的財務表現、業務和運營,包括製造業-半導體、供應鏈、研發活動和管線項目等的影響,以及對我們業務的其他潛在影響;
我們的進展持續建設和利用全球商業基礎設施;
競爭產品對ONPATTRO、AMVUTTRA、GIVLAARI、OXLUMO、Leqvio和fitusiran的商業成功可能造成的影響,以及我們的產品候選者,以及關於Leqvio或fitusiran,我們的合作伙伴,與這些產品競爭的能力;
我們管理增長和營業費用的能力;
我們對我們的5年 規劃和計劃的看法 賽諾菲安萬特P5x25 策略,以及我們實現與該策略相關的指標的意圖,包括在2025年底成爲一家頂級生物科技公司的能力以及成功執行我們的 賽諾菲安萬特P5x25 策略;
我們相信我們目前的現金餘額應該能夠實現自給自足的資金狀況,而無需未來的股權融資;
根據我們當前的運營計劃,我們對我們現有的現金、現金等價物以及可交易的股權和債券證券所能支持我們運營的時間長度的期望。
我們依賴第三方進行產品的開發、製造和分銷;
關於我們公司合作的期望,包括現有或未來協議項下的潛在授權費、里程碑和版稅支付。
3

目錄
我們獲取、維護和保護知識產權的能力;
我們吸引和保留合格的關鍵管理人員和科學家、開發、醫療和商業人員、顧問和顧問的能力;
訴訟結果,包括我們針對輝瑞公司,BioNTech SE和Moderna公司的專利侵權訴訟,以及其他法律訴訟或政府調查的結果;
美國和其他國家的監管發展;
法律和規章的影響;
與我們的競爭對手和我們所在的行業有關的發展;
我們有能力滿足支付義務,並支付利息,或者再融資我們的債務,包括可轉換債券,或者在可轉換債券轉換時進行現金支付,如有必要;和
我們對封頂看漲交易的影響效果以及期權交易對手或其各自關聯公司預期的市場活動。
這些前瞻性聲明反映了管理層對未來事件、我們的業務和未來財務表現的當前觀點,並涉及已知和未知的風險、不確定性和其他因素,這些因素可能導致我們的實際結果、業績或成就與這些前瞻性聲明所表達或暗示的任何未來結果、業績或成就顯着不同。可能導致實際結果與當前預期存在實質差異的因素包括但不限於,本季度報告表格10-Q中的第II部分第1A條「風險因素」和其他部分描述的內容。本季度報告表格10-Q的其他部分可能包含可能對我們的業務和財務表現產生不利影響的額外因素。此外,我們處於極具競爭性和快速變化的環境中。新的風險因素不時出現,管理層無法預測所有風險因素,我們也無法評估所有風險因素對我們的業務可能造成的影響,或者單個因素或多個因素的結合可能導致實際結果與任何前瞻性聲明所含內容存在實質差異的程度。考慮到這些不確定性,您不應過分依賴這些前瞻性聲明。除法律規定外,我們不承擔更新或修訂這些前瞻性聲明的任何理由的義務,即使將來提供新信息。但是,建議您查閱我們向證券交易委員會(SEC)提交的報告中作出的任何進一步披露。

4

目錄

第一部分 財務信息
項目1. 基本報表(未經審計)

ALNYLAm製藥公司。
簡明合併資產負債表
2024年4月27日
(未經審計)


2024年9月30日2023年12月31日
資產
流動資產:
現金及現金等價物$1,099,920 $812,688 
有價證券1,671,993 1,615,516 
可變現股份8,322 11,178 
2,687,823 353,852 327,787 
庫存75,987 89,146 
預付費用和其他流動資產145,350 126,382 
總流動資產3,355,424 2,982,697 
物業、廠房和設備,淨值506,997 526,057 
經營租賃權使用資產196,408 199,732 
受限投資68,592 49,391 
其他77,618 72,003 
總資產$4,205,039 $3,829,880 
負債和股東權益(赤字)
流動負債:
應付賬款$70,805 $55,519 
應計費用946,168 713,013 
經營租賃負債42,144 41,510 
遞延收入71,030 102,753 
與未來版稅銷售相關的負債90,516 54,991 
流動負債合計1,220,663 967,786 
經營租賃負債,減:流動部分
236,030 243,101 
遞延收入,減去當前部分淨額1,012 188,175 
可轉換債券1,023,654 1,020,776 
與未來版稅銷售有關的負債,減去當前部分1,333,849 1,322,248 
其他負債357,477 308,438 
負債合計4,172,685 4,050,524 
承諾和可能的賠償(注13)
股東權益(赤字):
優先股,$0.00010.015,000授權股數爲 截至2024年9月30日和2023年12月31日,已發行和流通的股份
  
普通股,每股面值爲 $0.0001;0.01250,000 128,841 截至2024年9月30日,已發行並流通的股份數量爲 125,794 截至2023年12月31日,已發行並流通股數爲。
1,289 1,259 
額外實收資本7,259,876 6,811,063 
累計其他綜合損失(24,826)(23,375)
累積赤字(7,203,985)(7,009,591)
股東權益(赤字)
32,354 (220,644)
負債和股東權益(赤字)總額
$4,205,039 $3,829,880 
隨附說明是這些簡明合併財務報表的一部分。
5

目錄
ALNYLAm製藥公司。
經簡化的合併利潤及損失表
綜合(損失)收益
2024年4月27日
(未經審計)
三個月已結束
九月三十日
九個月已結束
九月三十日
2024202320242023
運營聲明
收入:
產品淨收入$420,146 $313,153 $1,195,397 $895,186 
合作淨收入57,387 427,472 403,273 469,778 
特許權使用費收入23,386 9,905 56,407 23,610 
總收入500,919 750,530 1,655,077 1,388,574 
運營成本和支出:
售出商品的成本81,980 79,473 203,864 196,241 
合作成本和特許權使用費3,925 4,836 16,689 28,307 
研究和開發270,926 253,179 826,063 732,274 
銷售、一般和管理220,993 199,175 680,187 597,523 
運營成本和支出總額577,824 536,663 1,726,803 1,554,345 
運營收入(虧損)(76,905)213,867 (71,726)(165,771)
其他(支出)收入:
利息支出(34,376)(30,893)(102,887)(89,883)
利息收入32,146 25,425 90,973 65,155 
其他費用,淨額(29,528)(57,658)(99,777)(105,331)
其他支出總額,淨額(31,758)(63,126)(111,691)(130,059)
所得稅前(虧損)收入(108,663)150,741 (183,417)(295,830)
所得稅準備金(2,907)(2,988)(10,977)(6,542)
淨(虧損)收入$(111,570)$147,753 $(194,394)$(302,372)
普通股每股淨(虧損)收益——基本$(0.87)$1.18 $(1.53)$(2.43)
普通股每股淨(虧損)收益——攤薄後$(0.87)$1.15 $(1.53)$(2.43)
加權平均普通股——基本128,590 125,220 127,159 124,667 
加權平均普通股——攤薄128,590 131,337 127,159 124,667 
綜合(虧損)收益表
淨(虧損)收入$(111,570)$147,753 $(194,394)$(302,372)
其他綜合收益(虧損):
有價證券的未實現收益9,078 1,878 4,783 3,978 
外幣折算收益(虧損)703 2,873 (6,327)8,356 
扣除稅款的固定福利養老金計劃30 (10)93 (19)
其他綜合收益總額(虧損)9,811 4,741 (1,451)12,315 
綜合(虧損)收入$(101,759)$152,494 $(195,845)$(290,057)

隨附說明是這些簡明合併財務報表的一部分。
6

目錄
ALNYLAm製藥公司。
股東權益(赤字)基本彙總報表
(以千爲單位)
(未經審計)
普通股額外的
實收資本
資本
累積的
其他
綜合
損失
累積的
$
總費用
股東的
權益(虧損)
股份數量
2023年12月31日的餘額125,794 $1,259 $6,811,063 $(23,375)$(7,009,591)$(220,644)
行使普通股期權,扣除稅款後淨額223 2 24,763 — — 24,765 
根據股權計劃發行普通股股票446 4 (4)— —  
股權補償費用— — 46,155 — — 46,155 
其他綜合損失
— — — (3,613)— (3,613)
淨虧損— — — — (65,935)(65,935)
2024年3月31日的餘額126,463 1,265 6,881,977 (26,988)(7,075,526)(219,272)
行使普通股期權,扣除稅款後淨額1,264 13 140,273 — — 140,286 
根據股權計劃發行普通股股票294 3 10,358 — — 10,361 
股權補償費用— — 90,096 — — 90,096 
其他綜合損失
— — — (7,649)— (7,649)
淨虧損— — — — (16,889)(16,889)
2024年6月30日的餘額128,021 1,281 7,122,704 (34,637)(7,092,415)(3,067)
普通股期權行權,扣除稅款後淨額785 8 90,560 — — 90,568 
根據股權計劃發行普通股股票35 — — — —  
股權補償費用— — 46,612 — — 46,612 
其他綜合收益— — — 9,811 — 9,811 
淨虧損— — — — (111,570)(111,570)
2024年9月30日餘額128,841 $1,289 $7,259,876 $(24,826)$(7,203,985)$32,354 


隨附說明是這些簡明合併財務報表的一部分。
7

目錄
ALNYLAm製藥公司。
股東權益(赤字)基本彙總報表
(以千爲單位)
(未經審計)
普通股額外的
實收資本
資本
累積的
其他
綜合
損失
累積的
$
總費用
股東的
$
股份數量
2022年12月31日餘額123,925 $1,240 $6,454,540 $(44,654)$(6,569,349)$(158,223)
行使普通股期權,扣除稅款269 3 26,415 — — 26,418 
根據股權計劃發行普通股股票47 — — — — — 
股權補償費用— — 41,136 — — 41,136 
其他綜合收益
— — — 5,530 — 5,530 
淨虧損— — — — (174,101)(174,101)
截至2023年3月31日的餘額124,241 1,243 6,522,091 (39,124)(6,743,450)(259,240)
行使普通股期權,扣除稅款372 4 38,111 — — 38,115 
根據股權計劃發行普通股股票288 3 9,981 — — 9,984 
股權補償費用— — 76,990 — — 76,990 
其他綜合收益
— — — 2,044 — 2,044 
淨虧損— — — — (276,024)(276,024)
截至2023年6月30日的餘額124,901 1,250 6,647,173 (37,080)(7,019,474)(408,131)
行使普通股期權,扣除稅款後246 2 24,896 — — 24,898 
根據股權計劃發行普通股股票307 3 (3)— —  
股權補償費用— — 64,873 — — 64,873 
其他綜合收益— — — 4,741 — 4,741 
淨收入— — — — 147,753 147,753 
截至2023年9月30日的餘額125,454 $1,255 $6,736,939 $(32,339)$(6,871,721)$(165,866)



隨附說明是這些簡明合併財務報表的一部分。
8

目錄
ALNYLAm製藥公司。
現金流量表簡明綜合報表
(以千爲單位)
(未經審計)
截至9月30日的九個月
20242023
經營活動現金流量:
淨虧損$(194,394)$(302,372)
用於調節淨損失與經營活動中使用的淨現金的非現金調整:
折舊和攤銷42,502 40,572 
與營運租賃相關的攤銷和利息累積34,714 32,486 
與未來版稅銷售相關的負債非現金利息支出91,834 78,918 
股票補償費用
180,439 179,686 
可交易股權證券的已實現和未實現虧損
2,856 17,711 
發展衍生負債公允價值變動100,499 67,895 
其他(32,228)15,088 
經營性資產和負債變動:
2,687,823 (27,042)(91,808)
庫存12,741 6,377 
預付款項和其他資產(22,052)(32,427)
應付賬款、應計費用及其他負債153,200 119,506 
經營租賃負債(37,837)(35,014)
遞延收入(218,882)37,333 
經營活動產生的現金流量淨額
86,350 133,951 
投資活動現金流量:
購買固定資產(25,183)(46,902)
購買有市場流通的證券(1,148,203)(1,234,344)
市場證券的銷售和到期1,128,656 1,189,990 
受限投資到期收益57,875 58,475 
受限投資的購買(77,075)(58,475)
其他投資活動 (4,438)
投資活動產生的淨現金流出
(63,930)(95,694)
籌集資金的現金流量:
行使股票期權和其他類型股權帶來的收益,淨額266,673 116,570 
(回報)來自開發衍生品的收款,淨額
(3,511)16,333 
籌資活動產生的現金淨額263,162 132,903 
匯率變動對現金、現金等價物及受限制資金的影響2,032 (4,506)
現金,現金等價物和受限制現金的淨增加額
287,614 166,654 
期初現金、現金等價物及受限制的現金814,884 868,556 
期末現金、現金等價物及受限制的現金$1,102,498 $1,035,210 
現金流補充披露:
支付的利息現金$55,248 $26,675 
隨附說明是這些簡明合併財務報表的一部分。
9

目錄
ALNYLAm製藥公司。
簡明合併財務報表附註
(未經審計)


1. 業務性質
Alnylam藥業公司(也被稱爲Alnylam,該公司,我們,我們的或我們)於2002年6月14日開始運營,是一家生物製藥公司,致力於開發和商業化基於核糖核酸干擾(RNAi)的新型治療方法。我們致力於實現建立多產品、全球化、商業化的生物製藥公司的公司戰略,擁有一個深厚且可持續的RNAi治療產品的臨床管線,爲未來增長提供強大支持,以及一個穩健的有機研究引擎以進行可持續創新,對患者有着巨大潛力的影響。自成立以來,我們一直專注於通過在RNAi領域建立和維護強大的知識產權地位、與領先的製藥和生命科學公司建立戰略合作伙伴關係、通過許可協議獲取收入,最終獨立或與戰略合作伙伴全球開發和商業化RNAi治療。我們將幾乎所有的精力都投入到業務計劃、研究、開發、製造和商業努力、收購、申請和擴展知識產權、招募管理和技術人員以及籌集資本。
在2021年初,我們推出了我們的策略,重點是計劃在2025年底轉型爲一家頂尖生物科技公司。 賽諾菲安萬特P5x25 憑藉這一策略,我們旨在通過可持續創新爲全球患者提供改變命運的罕見病和常見病藥物,同時實現卓越的財務表現。 賽諾菲安萬特P5x25憑藉這一策略,我們旨在通過可持續創新爲全球患者提供改變命運的罕見病和常見病藥物,同時實現卓越的財務表現。
截至2024年9月30日,我們有 五個營運部門:獵鷹創意集團、PDP、Sierra Parima、目的地運營和Falcon's Beyond Brands,所有這些板塊均爲可報告板塊。公司的首席營運決策者是執行主席和首席執行官,他們評估財務信息以做出營運決策、評估財務表現和分配資源。營運板塊基於產品線組織,對於我們的基於位置的娛樂板塊,根據地理位置組織。營運板塊的結果包括直接歸屬於板塊的成本,包括項目成本、工資和與工資有關的開支以及與業務板塊運營直接相關的間接費用。未分配的企業費用,包括高管、會計、財務、市場營銷、人力資源、法律和信息技術支持服務、審計、稅收企業法律開支的工資和相關福利,作爲未分配的企業開銷呈現,成爲報告板塊的總收入(虧損)和公司未經審計的彙總財務報表結果之間的調節項。 營銷的產品,包括 之一 由合作伙伴商業化的產品,以及多個處於後期研究階段的項目正在朝着潛在商業化方向發展。我們目前主要在美國和歐洲銷售,從商業化產品ONPATTRO、AMVUTTRA、GIVLAARI和OXLUMO產生全球產品收入。 四個 商業化產品ONPATTRO、AMVUTTRA、GIVLAARI和OXLUMO帶來了全球產品收入,主要在美國和歐洲銷售。
2. 報告範圍和合並財務報表原則
Alnylam的附註簡明一體化基本報表未經審計,根據美國通用會計準則編制,適用於中期,管理層認爲,已包括所有必要的正常和重複調整,以公正陳述所報期間的經營結果。我們的簡明一體化基本報表也是基本一致的基礎上編制的,並應與截至2023年12月31日的經過審計的公司財務報表結合閱讀,這些報表包括在2024年2月15日提交給證券交易委員會的10-k表格中。年末的簡明一體化資產負債表數據是從我們的經審計財務報表中獲得的,但未包括美國通用會計準則所要求的所有披露。任何中期期間的營運結果並不能必然反映其他中期期間或整個財政年度的營運結果。
附表中的簡明合併財務報表反映了Alnylam及其全資子公司的運營情況。所有公司間帳戶和交易已經被剔除。
我們的重要會計政策在2023年12月31日結束的《年度報告》中的基本報表附註2中描述。在2024年9月30日結束的九個月期間,我們的重要會計政策沒有實質性變化。
使用估計
根據GAAP的要求,財務報表的編制需要管理層進行估計和假設,這些估計和假設會影響資產和負債的報告金額,以及披露跟日期爲準的簡明綜合財務報表中的或有資產和負債,以及報告期間營業收入和費用的金額。在我們的簡明綜合財務報表中,我們使用與庫存估值和相關準備金、未來版稅銷售相關責任、發展衍生工具負債、所得稅、遞延所得稅資產估值準備、營業收入確認、研發費用和股權報酬支出相關的估計和假設。我們的估計基於歷史經驗和我們認爲合理的各種其他假設。實際結果可能與這些估計有所不同。估計值的變化體現在變爲已知的期間的報告結果中。
流動性
根據我們當前的運營計劃,我們相信截至2024年9月30日,我們的現金、現金等價物和可市場化證券將足以滿足本季度在表格10-Q上報告文件的提交日期後至少未來12個月的營運資金和運營需求。
10

目錄
ALNYLAm製藥公司。
簡明合併財務報表附註
(未經審計)
最近的會計聲明
2023年12月,財務會計準則委員會(Financial Accounting Standards Board,簡稱FASB)發佈了會計準則更新(Accounting Standards Update,簡稱ASU)2023-09,關於income tax披露的改進,要求實體披露有關其有效稅率調整的細分信息,以及有關各司法管轄區所支付所得稅的擴展信息。披露要求將按照前瞻性的方式應用,有選擇性地可以追溯地應用它們。本標準自2024年12月15日後開始的財政年度生效,允許提前採納。我們目前正在評估與這一新標準相關的披露要求。
2023年11月,FASB發佈了ASU 2023-07《分部報告》(第280號課題):改進報告部門披露,旨在通過額外披露有關重要部門費用的信息,改善可報告部門披露要求。該標準將於2023年12月15日後開始的財政年度生效,並適用於2024年12月15日後開始的財政年度的中期時段,可提前採用。修訂內容應適用於基本報表中呈現的所有以前期間。我們目前正在評估與這一新標準相關的披露要求。
3. 淨產品收入
根據產品銷售地域板塊劃分的淨產品收入包括以下內容:
三個月已結束
九月三十日
九個月已結束
九月三十日
(以千計)2024202320242023
ONPATTRO
美國$16,207 $21,869 $54,858 $77,246 
歐洲24,327 50,371 106,091 166,442 
世界其他地區9,759 9,349 35,805 31,852 
總計50,293 81,589 196,754 275,540 
AMVUTTRA
美國168,658 113,508 447,359 288,990 
歐洲65,140 19,417 165,633 40,590 
世界其他地區24,792 15,755 70,948 53,004 
總計258,590 148,680 683,940 382,584 
GIVLAARI
美國40,372 37,009 120,328 102,496 
歐洲16,281 12,430 47,910 40,952 
世界其他地區14,390 4,709 22,988 16,505 
總計71,043 54,148 191,226 159,953 
OXLUMO
美國14,933 9,713 44,009 27,564 
歐洲19,977 15,086 61,907 40,611 
世界其他地區5,310 3,937 17,561 8,934 
總計40,220 28,736 123,477 77,109 
產品淨收入總額$420,146 $313,153 $1,195,397 $895,186 
11

目錄
ALNYLAm製藥公司。
簡明合併財務報表附註
(未經審計)
以下表格顯示了與我們淨產品收入相關的應收賬款餘額:
(以千爲單位)截至2022年9月30日,
2024
截至12月31日,
2023
包括在「應收賬款淨額」中的應收款項$266,380 $210,097 

4. 合作產生的淨收入
合作中的淨收入包括以下內容:
截至9月30日的三個月截至9月30日的九個月
(以千計)2024202320242023
羅氏
$16,289 $311,328 $107,475 $311,328 
再生元製藥37,948 80,254 272,141 97,407 
諾華股份公司2,936 18,381 19,756 41,941 
其他214 17,509 3,901 19,102 
總計$57,387 $427,472 $403,273 $469,778 
    
以下表格顯示了與我們的合作協議相關的應收賬款和合同責任的餘額:
(以千爲單位)截至2024年9月30日截至2023年12月31日
應收賬款包括在「應收賬款淨額」中$64,576 $99,576 
合同責任包括在「遞延營業收入」中$72,046 $290,763 
我們分別在2024年6月30日止的三個和六個月以及2023年6月30日止的三個和六個月中確認了營業收入分別爲$百萬和$百萬,這些營業收入在適用期的開始時包括在合同責任負債餘額中。19.5萬美元和248.6 在2024年9月30日結束的三個月和九個月中,營業收入分別爲1000萬美元和3000萬美元。50.5萬美元和42.0 在2023年9月30日結束的三個月和九個月中,營業收入分別爲1000萬美元和3000萬美元,這些金額包含在適用期間開始時的合同責任餘額中。
爲了判斷從合同責任中確認的營業收入,我們首先將營業收入分配到在期初未償還的個別合同責任餘額,直到營業收入超過該餘額爲止。如果在後續期間收到了額外費用,我們假定在報告期內確認的所有營業收入首先適用於期初合同責任,而不是部分適用於當期的新費用。
下表提供我們直接歸因於合作協議的研發費用,按類型和合作夥伴承擔的,認可的淨收益。
截至9月30日的三個月
20242023
(以千爲單位)
臨床和製造業-半導體
其他服務其他
臨床和製造業-半導體
其他服務其他
羅氏公司
$27,200 $317 $239 $ $ $ 
再生元製藥公司19,796 3,216 4,844 8,672 1,954 8,313 
其他3,488   1,047 1,139 1,179 
總費用$50,484 $3,533 $5,083 $9,719 $3,093 $9,492 
12

目錄
ALNYLAm製藥公司。
簡明合併財務報表附註
(未經審計)
截至9月30日的九個月
20242023
(以千爲單位)
臨床和製造業-半導體
外部服務其他
臨床和製造業-半導體
外部服務其他
羅氏公司
$63,838 $6,428 $1,807 $ $ $ 
再生元製藥公司36,591 10,449 13,803 27,144 4,104 27,006 
其他7,079 89 949 1,444 1,323 1,944 
總費用$107,508 $16,966 $16,559 $28,588 $5,427 $28,950 
上述表格中包括的協議所發生的研發費用包括以下費用:(i)臨床和製造費用,包括臨床和臨床前產品的製造,(ii)外部服務,包括諮詢服務和實驗室用品和服務,以及(iii)其他費用,包括專業服務、設施和間接成本分攤,以及作爲我們向合作方開具賬單的補償和相關成本的合理估計,我們認定從合作中獲得的淨收入。截至2024年和2023年9月30日的三個月和九個月,我們未產生與我們的合作協議相關的重大銷售、管理和行政費用。
產品合作
羅氏公司
2023年7月21日,或有效日期,我們與F. Hoffmann-La Roche Ltd.和Genentech, Inc.,即Roche公司,簽訂了一項合作和許可協議,即Roche協議,根據該協議,我們和Roche成立了一個全球戰略合作伙伴關係,共同開發zilebesiran。Zilebesiran是我們正在研究的小干擾RNA(siRNA)治療藥物,針對表達在肝臟中的血管緊張素原,目前處於用於治療高血壓的2期臨床開發階段。
根據羅氏協議,我們授予羅氏公司(i)在全球開發zilebesiran並在美國商業化zilebesiran的共享權利,稱爲共同商業化領土,(ii)在美國以外商業化zilebesiran的獨家權利,稱爲羅氏領土,以及(iii)在羅氏領土以外開發和商業化zilebesiran時製造zilebesiran的非獨家權利。 在與羅氏的協議中,羅氏公司向我們預付了不可退還的金額,共$310.0股票回購活動以及因員工基於股票的補償目的而重新發行國庫股的情況如下:
我們領導全球茨嘧利珠單抗的臨床開發。我們對四十%的開發成本負責40羅氏對全球茨嘧利珠單抗獲得監管批准的開發活動產生的其餘六十%的開發成本負責60如果需要額外的開發活動,我們和羅氏將在合作開發領域平均分享所有相關開發活動產生的費用50/50羅氏負責在主要支持羅氏領域監管批准的開發活動方面產生的所有費用50/50在合作發展領域,我們和羅氏將共同商業化茨嘧利珠單抗,分享平等的利潤和損失(包括商業化成本)
Roche有權在事先書面通知後因任何原因終止Roche協議;但如果終止發生在第一個開發里程碑達成後第三個開發里程碑達成之前,Roche需要支付我們一筆終止費用$50.0 百萬。此外,雙方均可因另一方的重大違約或破產而終止Roche協議,但需遵守補救期。除非根據其條款提前終止,否則Roche協議將在逐國有效期到期時繼續有效(a)在Roche領Territory,在適用國家的適用版稅期限到期後;以及(b)在合作領Territory,在合作努力的期限到期後。
我們評估了羅氏協議,並得出結論,羅氏協議中的元素符合會計準則 codification,即 ASC 606, 與客戶簽訂合同的營業收入 以及 ASC 808, 合作安排.
截至生效日期,我們在羅氏協議中確認了以下承諾,這些承諾已根據ASC 606範圍進行評估:(i)在合作推廣領域開發席替比沙雞全球範圍內和在合作推廣領域內推廣席替比沙雞的專屬許可,以及在羅氏領域內僅用於開發和推廣席替比沙雞的生產席替比沙雞的非獨家許可,以及在羅氏領域內推廣席替比沙雞的獨家許可,統稱爲羅氏許可責任,(ii)開發服務,包括製造
13

目錄
ALNYLAm製藥公司。
簡明合併財務報表附註
(未經審計)
支持齊列貝西單獲得監管批准的臨床供應,稱爲羅氏發展服務義務,以及(iii)齊列貝西單現有製造工藝的技術轉移,稱爲羅氏技術轉移義務。 根據羅氏協議下的履約義務合稱爲羅氏履約義務。
我們還評估了Roche協議中所概述的某些期權是否代表會產生履約義務的實質權利,並得出結論稱,這些期權均未賦予Roche實質權利,因此並未被視爲Roche協議中獨立的履約義務。
我們評估了上述承諾,並確定羅氏的許可義務、羅氏開發服務義務和羅氏技術轉讓義務反映了一種供應商-客戶關係,因此代表了《ASC 606》範圍內的履約義務。羅氏許可義務被視爲功能性知識產權,與合同下其他承諾有區別,因爲羅氏可以獨立或與其他現有資源一起受益於這些許可。由於許可同時交付,它們在合同生效時被視爲一個履約義務。羅氏開發服務義務被視爲與羅氏在協議生效時由我們轉讓的許可一起受益的獨立義務。預計開發服務不會顯著修改或定製最初的知識產權,因爲zilebesiran在合同生效時處於2期臨床開發階段。羅氏技術轉讓義務被視爲獨立的義務,因爲羅氏可以受益於我們在協議生效時轉讓的製造許可,考慮到我們RNAi平台的進展以及我們利用第三方合同製造組織製造zilebesiran。因此,每個都代表了《ASC 606》範圍內的合同與客戶之間在合同生效時的分開履約義務。
我們認爲在美國與Roche合作共同推廣zilebesiran所涉及的合作活動是ASC 808範圍內的一個獨立帳戶單位,因爲我們和Roche都是商業化活動的積極參與者,且承擔着取決於安排中活動的商業成功的重大風險和回報。
我們在Roche協議簽訂之初按照ASC 606確定的交易價格爲$857.0百萬美元,包括$310.0 百萬美元的預付款和$547.0 百萬美元的額外變量考慮,歸因於從Roche履約義務相關的開發和製造服務以及技術轉讓的成本補償。我們確定,在簽訂時,與開發和監管里程碑相關的任何變量考慮被認爲是完全受限制的,並因此由於與這些潛在支付相關的高度不確定性和風險,我們確定不能斷言發生累積收入確認金額的重大逆轉的概率不會發生。我們還確定,版稅和銷售里程碑僅涉及知識產權的許可,因此根據ASC 606的按銷售或使用量計提的版稅異常情況被排除在交易價格之外。
我們在初次確認時爲每個羅氏履行義務開發了估計的獨立銷售價格,目的是確定如果按獨立基準定期銷售這種物品的價格。我們主要根據與每個基礎許可證或活動相關的預期未來現金流的概率加權現值來開發羅氏許可義務的估計獨立銷售價格。在開發這些估計時,我們在確定預測的收入方面進行了判斷,考慮了適用的市場條件和相關的實體特定因素,成功的概率,開發zilebesiran所需的時間以及折現率。我們主要根據執行該服務所需的努力程度以及全職員工成本和所需資源的預期投入加上合理的利潤,爲包括在羅氏開發服務義務和羅氏技術轉讓義務中的服務和臨床供應開發了估計的獨立銷售價格。
我們將與羅氏開發服務義務和羅氏技術轉讓義務相關的可變補償分配給每個履約義務,因爲可變支付的條款與我們滿足履約義務的努力有關,並且將可變補償的全部金額分配給各自的履約義務與合同中所有履約義務和付款條件一起考慮時,與ASC 606的分配目標一致。 我們將金額爲$的固定預付款項完全分配給Roche許可義務。310.0百萬完全分配給羅氏許可義務,因爲固定補償的價值與預期的剩餘開發和監管里程碑、基於銷售的里程碑和版稅的總和,這些在簽訂時要麼受到約束,要麼受到銷售或使用量基礎的特例約束,大致等於羅氏許可義務的獨立銷售價格。 因此,將固定預付款項全部分配給Roche許可義務是與考慮合同中所有履約義務和付款條件時ASC 606的分配目標一致。
羅氏許可義務在將許可證轉讓給羅氏時達成,許可證的控制權在生效日期轉移,羅氏可以開始使用和受益於這些許可證。對於羅氏的發展
14

目錄
ALNYLAm製藥公司。
簡明合併財務報表附註
(未經審計)
服務義務,我們使用基於已發生成本相對於義務總估計成本的輸入方法,按季度基礎分攤比例業績,通過確定已發生努力佔預計支出總努力的百分比。這個比率應用於分配給義務的交易價格。在制定估計過程中,管理層已經運用了重大判斷。我們在每個報告期結束時重新評估交易價格。
截至2024年9月30日,總交易價格確定爲$922.0百萬美元,比2023年12月31日增加$65.0百萬美元。此增長是因爲在KARDIA-3第2期臨床試驗中首位接受劑量的患者達到了發展里程碑。
以下的表格提供了分配給每項履約義務的交易價格總結,以及期間內的營業收入活動,單位爲千美元:
營業收入確認期間
交易價格分配截至9月30日的三個月截至9月30日的九個月
履行責任截至2024年9月30日2024202320242023
Roche許可責任
$375,000 $ $310,000 $65,000 $310,000 
Roche開發服務責任
545,000 14,884 200 34,832 200 
羅氏科技轉讓義務
2,000     
$922,000 $14,884 $310,200 $99,832 $310,200 
截至2024年9月30日,分配給羅氏履約義務但尚未履行的交易價格總額爲$488.2 百萬,預計將在羅氏協議期間履行服務時予以確認。
再生元製藥公司(NASDAQ:REGN)之間的合作
概述
2019年,我們與再生元製藥公司(Regeneron Pharmaceuticals, Inc.)達成全球戰略合作,旨在發現、開發和商業化RNAi治療技術,針對眼部、中樞神經系統(CNS)以及肝臟中的治療靶點,涉及廣泛的疾病範圍。這項合作被稱爲再生元合作計劃(Regeneron Collaboration)。再生元合作計劃受《再生元主協議》管轄。爲配合再生元主協議,我們與再生元簽署了以下協議:(i)覆蓋繼續開發用於C5亞單位介導疾病的C5 siRNA cemdisiran的合作協議(作爲單藥物治療),即C5合作協議(C5 Co-Co Collaboration Agreement),以及(ii)評估抗C5抗體-siRNA組合用於治療C5亞單位介導疾病的許可協議,包括評估再生元的pozelimab和cemdisiran組合,即C5許可協議(C5 License Agreement)。由於這些協議是一起談判的,因此《主協議》,《C5合作協議》和《C5許可協議》被視爲一項協議安排。
2022年11月,Regeneron行使了C5 Co-Co合作協議下的選擇權,選擇放棄對cemdisiran單藥進一步的開發和商業化。由於Regeneron決定放棄,根據C5 Co-Co合作協議授予給Regeneron的許可權恢復到我們手中,我們有權繼續開發和商業化cemdisiran單藥,Regeneron不再共同承擔任何單藥治療項目的費用。Regeneron仍有資格獲得根據銷售淨額而定的兩位數特許權使用費作爲cemdisiran單藥的一部分。
2024年6月,我們簽署了經修訂和重新簽署的C5許可協議,即修訂後的C5許可協議,該協議終止了C5 Co-Co合作協議,並授予Regeneron關於單獨使用cemdisiran的全球許可以及與抗C5抗體結合使用cemdisiran的許可。通過修訂後的C5許可協議,Regeneron現在將獨自負責開發、製造和商業化cemdisiran作爲單藥療法以及與抗C5抗體結合使用的情況。作爲修訂後的C5許可協議的一部分,我們將爲Regeneron提供cemdisiran的製造技術轉讓服務。Regeneron向我們提供了一筆預付款$10.0百萬美元,我們將在cemdisiran作爲單藥療法獲得監管批准後收到一定的里程碑付款,以及銷售淨額的分層雙位數比例的特許使用費。修訂後的C5許可協議未改變我們收到低雙位數特許使用費和最高$325.0百萬美元的商業里程碑支付的權利,如果cemdisiran被用作組合產品的一部分。
根據Regeneron合作協議的條款,我們將與Regeneron獨家合作,爲眼部和中樞神經系統疾病發現RNAi治療藥物,最初的研究期限長達 七年,我們稱之爲初始
15

目錄
ALNYLAm製藥公司。
簡明合併財務報表附註
(未經審計)
Regeneron有權將初始研究期延長(稱爲研究期延長期,與初始研究期一起構成研究期),最長延長 月內。2023年和2022年的三個和九個月期權授予均以授予日公司普通股的公允價值相等的行權價格授予,並且是非法定股票期權。,需支付研究期延長費用$300.0 百萬美元。此外,Regeneron合作還涵蓋了一些特定的RNAi治療計劃,旨在靶向肝臟中表達的基因。
Regeneron在所有目標眼部疾病項目的開發和商業化方面處於領先地位(遵循有限的例外情況),因許可協議的條款,我們有權獲得某些潛在的里程碑和版稅支付,各方已就協議形式達成一致意見。我們與Regeneron在中樞神經系統和肝臟項目上輪流領導,領導方保留全球開發和商業責任。對於這類中樞神經系統和肝臟項目,我們和Regeneron在領先候選者選擇時有選擇進入合作協議的權利,各方已就協議形式達成一致意見,根據該協議,兩家公司將平等分擔所有開發和商業化活動下的成本和利潤。如果非領導方選擇不與關於某一中樞神經系統或肝臟項目進入合作協議,我們和Regeneron將就該項目簽署許可協議,而領導方將成爲許可協議的「受讓方」。如果中樞神經系統或肝臟項目的領導方選擇不進入合作協議,那麼我們和Regeneron將就該項目簽訂許可協議,並且項目的領導權將轉移到另一方,之前的非領導方將成爲許可協議的「受讓方」。
根據Regeneron主協議,我們仍有資格在完成某些特定標準的早期臨床開發時,獲得額外的$100.0百萬的里程碑支付。此外,我們和Regeneron正在推進在初始研究期間提名的項目,Regeneron有權在此期間每年提名多達 六個 個額外目標。對於這些項目,Regeneron將在項目啓動時爲我們提供$2.5百萬的資金,並在確定首選候選人時另外提供$百萬。如果Regeneron行使延長研究期限的選擇權,Regeneron將保留在每年提名多達2.5個額外目標的權利,而我們仍有資格獲得$ 六個 million的獎勵。2.5每次項目啓動時獲得100萬美元的資金,並在研究期延長期間每次首席候選者確定時額外獲得100萬美元。2.5在研究期延長期間,每次首席候選者確定時獲得100萬美元。
對於隨後簽訂的任何許可協議,被許可方通常將對與合作產品開發和商業化有關的自身成本和費用負責。被許可方將向許可方支付總計高達$的某些發展和/或商業化里程碑付款。150.0 百萬美元的每個合作產品。此外,在根據許可協議在適用合作產品的首次商業銷售後,被許可方需要根據合作產品的年度淨銷售額向許可方支付一定層級的版稅支付,從低兩位數到百分之雙位數不等,受慣例性減少約束。 20,基於合作產品的年度淨銷售額向許可方支付一定層級的版稅支付,從低兩位數到某個百分數,受慣例性減少約束。
對於隨後簽訂的任何合作協議,我們和再生元將平均分擔所有開發和商業化活動的成本和利潤。我們的成本分擔款項將被確認爲企業損益表中研發費用的減少。如果一方行使退出權利,主導方將負責與適用合作協議中的合作產品的開發和商業化相關的所有費用,但在特定節點之前仍需繼續分擔成本。如果一方行使退出權利,在適用的合作協議下的合作產品首次商業銷售後,主導方將需要根據合作產品的年度淨銷售總額和行使退出權利的時間,向另一方支付一定級別的特許權使用費,金額從低兩位數起,直至 20,根據合作產品的年度淨銷售額和行使退出權利的時間,根據慣例折扣和退出過渡成本的減少,主導方將向另一方支付一定級別的特許權使用費。
合同修改
2024年6月,我們確定經過修改的C5許可協議不符合ASC 606要求,無法將合同修改作爲單獨合同進行覈算,因爲爲額外獨立商品和服務交換的對價未反映獨立銷售價格。因此,我們將修改後的C5許可協議和Regeneron主協議視爲一個合併合同。修訂日期確定爲2024年6月經修改後的C5許可協議生效日期。
我們在合同修改後的履約義務包括:(i)研究許可和研究服務,合稱爲研究服務義務;(ii)用於聯合療法的cemdisiran的全球許可和製造及開發服務義務,合稱爲C5許可義務;(iii)用於單獨療法的cemdisiran的全球許可,稱爲C5單獨療法義務,以及(iv)現有cemdisiran製造工藝的技術轉移,稱爲Regeneron技術轉移義務。
經修訂的C5許可協議未更改研究服務義務或C5許可義務,這兩者在我們與Regeneron全球戰略合作初始階段即爲履約義務。C5修訂許可協議導致 兩個 額外的履約義務是
16

目錄
ALNYLAm製藥公司。
簡明合併財務報表附註
(未經審計)
C5單藥療法義務和Regeneron科技轉讓義務。 C5單藥療法義務被視爲功能知識產權,與Regeneron的其他承諾不同,因爲Regeneron可以單獨或與其他現有資源一起從cemdisiran單藥療法許可證中受益,且該許可證可與合同中的其他承諾分開識別。Regeneron科技轉讓義務與衆不同,因爲Regeneron可以從我們轉讓的cemdisiran單藥療法許可證中受益,而無需進行技術轉讓,因爲cemdisiran處於臨床開發的高級階段,並且我們利用第三方合同製造組織來製造cemdisiran。因此,C5單藥療法義務和Regeneron科技轉讓義務各代表一個獨立的履約義務。
截至修改日期,我們確定了一項新的交易價格爲$329.7 百萬,這代表了修改日期未結轉營業收入剩餘的$260.3 百萬,這包括了與研究服務義務、C5許可權義務和Regeneron科技轉讓義務相關的預計退款和里程碑所涉及的變量收入$59.4 百萬,以及與修訂後的C5許可協議相關的前期支付$10.0百萬。我們將$59.4 百萬的變量收入分配給了各自的履約義務,因爲變量付款條件與我們履行履約義務的努力直接相關,並且完全將變量收入分配給各自的履約義務符合ASC 606的分配目標,考慮合同中的所有履約義務和付款條款。
我們確定與監管里程碑有關的任何可變報酬被認爲是完全受限制的,因此由於與這些潛在付款相關的高度不確定性和風險,我們從交易價格中排除。我們確定我們無法斷言發生累積營業收入金額顯著逆轉的可能性不大。我們確定版稅和銷售里程碑僅與知識產權許可有關,因此根據ASC 606的銷售或使用爲基礎的版稅例外被排除在交易價格之外。
截至修改日期,每項履約義務的交易價格如下,單位:千美元:
履行責任單獨銷售價格
固定代價
分配的變量代價
總交易價格
研究服務義務$78,820 $45,469 $30,000 $75,469 
C5許可義務$53,745 31,004 25,386 56,390 
C5單藥物治療義務
$332,000 191,520  191,520 
Regeneron 科技轉讓義務
$4,000 2,307 4,000 6,307 
$270,300 $59,386 $329,686 
固定考慮已根據各項義務的相對估計獨立銷售價格分配,管理層在此基礎上進行了重大判斷。我們開發了剩餘研究服務義務、剩餘C5許可義務和新的Regeneron技術轉讓義務的估計獨立銷售價格,主要基於執行服務所需的工作程度、全職員工和預期資源的成本,以及合理的利潤率。我們以基於調整市場評估方法的賈邁希尼噶單藥物許可證的獨立銷售價格來開發,在此方法中建立了一個貼現現金流模型,以確定作爲單藥物治療的賈邁希尼噶在商業期間的預期收益,調整爲成功概率。
交易價格爲$191.5 分配給C5單獨療法責任履行義務的交易價格立即被確認,因爲此義務在將許可證轉移給Regeneron時已得到滿足。許可證的控制權於2024年6月轉移,Regeneron可以開始使用並從許可證中受益。
在合同修改日期確認了剩餘的研究服務和剩餘的C5許可義務的累積趕上調整,以反映修改後的進度和交易價格。剩餘的研究服務和剩餘的C5許可義務的累積趕上調整並不重大。
對於研究服務義務、C5許可義務和Regeneron科技轉讓義務,我們使用基於已發生成本與各項確定義務總估成本的相對比例的輸入方法,隨時間測算比例績效,確定發生努力的比例佔我們預計將耗費的總努力的百分比。該比例應用於分配給各項義務的交易價格。管理層在制定我們的估計過程中進行了重要判斷。對這些估計的任何更改將作爲累積補充,在更改時期予以確認。我們將在每個報告期結束時和在
17

目錄
ALNYLAm製藥公司。
簡明合併財務報表附註
(未經審計)
2024年9月30日,總交易價格確定爲$166.7百萬。根據該協議確認的營業收入被列爲合作營業收入。
以下表格總結了分配的交易價格、資產負債表日期的遞延收入,以及在期間內對未滿足的績效義務而確認的營業收入,單位:千美元:
交易價格分配遞延收益
履行責任截至2022年9月30日,
2024
截至2022年9月30日,
2024
截至12月31日,
2023
研究服務義務$100,583 $45,474 $63,400 
C5許可證義務60,191 22,102 27,500 
再生達科技轉讓義務
5,913 2,307  
$166,687 $69,883 $90,900 
營業收入確認期間
截至9月30日的三個月截至9月30日的九個月
履行責任2024202320242023
研究服務義務$11,100 $73,000 $29,800 $66,700 
C5許可證義務8,400 700 18,900 6,000 
$19,500 $73,700 $48,700 $72,700 
截至2024年9月30日,分配給未滿足的研究服務義務、C5許可義務和再生元科技轉讓義務的交易價格總額爲$133.3百萬美元,預計將通過再生元合作期間的服務履行而確認。與再生元合作相關的遞延營業收入根據預計確認收入的期間在綜合資產負債表中分類爲流動或非流動資產。
諾華製藥
2013年與The Medicines Company合作
2013年2月,我們與The Medicines Company(MDCO)簽訂了一項許可和合作協議,根據該協議,我們授予MDCO獨家全球使用權,開發、生產和商業化針對蛋白酶原轉化酶絲裂原/裂孢菌素Kexin類型9的RNAi療法,用於治療高膽固醇血癥和其他人類疾病,包括inclisiran。我們稱這份協議截至日爲MDCO許可協議。2020年,諾華製藥(Novartis AG)完成了對MDCO的收購,並承擔了MDCO在MDCO許可協議下的所有權利和義務。
截至2024年9月30日,我們已賺取$120.0百萬里程碑,我們可能有資格獲得額外的$60.0百萬商業化里程碑。此外,根據諾華、其關聯公司和被許可方年度全球淨銷售額的百分比,我們有資格獲得不同比例的版稅,但根據特定情況下會有折扣。 100%至5%的版稅 20%基於諾華、其關聯公司和被許可方所授權產品的年度全球淨銷售額,根據特定情況會減少版稅。
其他
除上述討論的合作協議外,我們還有其他各種合作協議,目前對我們的業務結果或財務狀況沒有單獨重大影響。根據這些協議的條款,我們可能需要支付,或者可能會收到,根據各種未來事件的發生而變動的額外金額(例如,根據各種發展和商業里程碑的實現),總體上可能是重大的。我們還可能發生或得到顯著的研發成本或獲得補償。此外,如果與這些合作相關的任何產品獲得銷售批准,我們可能需要支付,或者可能會收到,未來銷售專利的 royalties。然而,這些金額的支付或收到取決於各種未來事件的發生。由於藥品開發的不確定性以及與藥物開發和商業化普遍相關的高失敗率,我們可能不會在所有現有的合作協議和許可協議(包括本附註中描述的協議)中收到任何此類支付。
18

目錄
ALNYLAm製藥公司。
簡明合併財務報表附註
(未經審計)
5. 公允價值計量
以下表格展示了我們的財務資產和負債的信息,這些信息是以可重複的方式按公平價值衡量的,並指示了我們用於判斷這種公允價值的估值技術的公允價值層次結構:
(以千爲單位)截至2024年9月30日在活躍市場中報價
(一級)
重要可觀察的輸入
(三級)
重要的不可觀察的輸入
非市場可觀察到的輸入(三級)
金融資產
現金等價物:
貨幣市場基金$182,594 $182,594 $ $ 
商業票據6,187  6,187  
美國國庫債券2,997  2,997  
有市場流通的債券證券:
美國國庫債券831,213  831,213  
美國政府贊助企業債券462,785  462,785  
企業債券322,758  322,758  
商業票據50,214  50,214  
市政債券5,023  5,023  
可變現股份8,322 8,322   
受限現金(貨幣市場所有基金類型)908 908   
總金融資產$1,873,001 $191,824 $1,681,177 $ 
財務負債
發展衍生工具責任$421,929 $ $ $421,929 

(以千爲單位)截至2023年12月31日在活躍市場中報價
(一級)
重要可觀察的輸入
(三級)
重要的不可觀察的輸入
非市場可觀察到的輸入(三級)
金融資產
現金等價物:
貨幣市場基金$166,059 $166,059 $ $ 
美國國庫債券30,712  30,712  
商業票據2,685  2,685  
企業債券762  762  
有市場的債務證券:
美國國庫債券862,022  862,022  
美國政府贊助企業債券441,341  441,341  
企業債券252,350  252,350  
商業票據56,216  56,216  
定期存單3,587  3,587  
可變現股份11,178 11,178   
受限現金(貨幣市場基金)1,210 1,210   
總金融資產$1,828,122 $178,447 $1,649,675 $ 
財務負債
發展衍生債務$324,941 $ $ $324,941 
截至2024年9月30日和2023年的九個月,有 資產或負債在三級財務資產或負債之間轉移。由於其短期到期,現金、應收賬款淨額、其他流動資產、應付賬款和應計費用在我們的簡明綜合資產負債表上反映的賬面金額近似於公允價值。
19

目錄
ALNYLAm製藥公司。
簡明合併財務報表附註
(未經審計)
6. 可交易債務證券
我們將多餘現金餘額投資於可交易債務證券,並在每份資產負債表日期呈現時,將所有債務證券投資分類爲可供出售,並作爲流動資產,因爲它們代表了用於當前經營的資金投資。在截至2024年9月30日或2023年止的三個月和九個月內,我們未記錄任何與我們的可交易債務證券相關的減值損失。
以下表格總結了我們的可交易債務證券:
截至 2024 年 9 月 30 日
(以千計)攤銷
成本
未實現收益總額
未實現虧損總額
公允價值
美國國債$831,019 $3,231 $(40)$834,210 
美國政府贊助的企業證券461,459 1,410 (84)462,785 
公司筆記320,957 1,823 (22)322,758 
商業票據56,401   56,401 
市政證券5,010 13  5,023 
總計$1,674,846 $6,477 $(146)$1,681,177 
截至 2023 年 12 月 31 日
(以千計)攤銷
成本
未實現收益總額
未實現虧損總額
公允價值
美國國債$892,237 $1,085 $(588)$892,734 
美國政府贊助的企業證券440,915 1,000 (574)441,341 
公司筆記252,487 945 (320)253,112 
商業票據58,901   58,901 
存款證3,587   3,587 
總計$1,648,127 $3,030 $(1,482)$1,649,675 
在簡明合併資產負債表中,根據分類劃分,我們的可交易債務證券的公平價值情況如下:
(以千爲單位)截至2024年9月30日截至2023年12月31日
有價證券$1,671,993 $1,615,516 
現金及現金等價物9,184 34,159 
總費用$1,681,177 $1,649,675 
7. 其他資產負債表詳細信息
庫存
庫存的元件總結如下:
(以千爲單位)截至2024年9月30日截至2023年12月31日
原材料$22,365 $23,346 
在製品
69,865 76,963 
成品23,126 25,123 
19,782
$115,356 $125,432 
截至2024年9月30日和2023年12月31日,我們的長期庫存分別爲$39.4萬美元和36.3 百萬,包括在我們的簡明合併資產負債表中的其他資產中,因爲我們預計它將在超出正常營運週期後被消耗。
20

目錄
ALNYLAm製藥公司。
簡明合併財務報表附註
(未經審計)
現金、現金等價物和受限制的現金
以下表格提供了現金、現金等價物和限制性現金的調解,這些金額在我們簡明的合併資產負債表中滙總,總金額顯示在簡明的現金流量表中。
截至2022年9月30日,
(以千爲單位)20242023
現金及現金等價物$1,099,920 $1,033,024 
其他資產中包括的限制性現金總額2,578 2,186 
在簡明合併現金流量表中顯示的現金、現金等價物和受限制現金總額
$1,102,498 $1,035,210 
其他綜合收益(虧損)累計額
以下表格總結了各項累積其他綜合損益的變動情況:
(以千爲單位)投資合資企業虧損定義受益養老金
計劃
債務的未實現收益(損失)
證券
外幣翻譯
調整
其他累計總計
綜合虧損
2023年12月31日的餘額$(32,792)$(2,753)$1,548 $10,622 $(23,375)
重新分類前的其他綜合損失
  (4)(6,327)(6,331)
重新分類的累計其他綜合損失中的金額
 93 4,787  4,880 
淨其他綜合收益(損失)
 93 4,783 (6,327)(1,451)
2024年9月30日餘額$(32,792)$(2,660)$6,331 $4,295 $(24,826)
(以千爲單位)合資創業公司投資損失定義受益養老金
計劃
債務未實現(損失)收益
證券
外幣翻譯
調整
全部綜合收益累計損失總額
2022年12月31日餘額$(32,792)$(1,092)$(9,470)$(1,300)$(44,654)
重新分類前綜合(損失)收益
  (10)8,356 8,346 
重新分類的累計其他綜合損失中的金額
 (19)3,988  3,969 
其他綜合損益的淨(虧)收益
 (19)3,978 8,356 12,315 
截至2023年9月30日的餘額$(32,792)$(1,111)$(5,492)$7,056 $(32,339)
從累積其他綜合(損失)收益中重新分類出來的金額與市場債務證券的結算和養老金義務的攤銷有關,這些金額記錄在綜合損益表中的其他費用淨額內。
8. 可轉換債務
2027年到期的可轉換優先票據
2022年,我們開始了美元的私募發行900.0本金總額爲百萬美元 12027年到期的可轉換優先票據或初始票據的百分比。2022年9月13日,此類發行的初始購買者行使了額外購買美元的選擇權135.0我們的總本金總額爲百萬美元 12027年到期的可轉換優先票據百分比或額外票據,加上初始票據統稱爲票據,使已發行和未償還的票據的本金總額達到美元1.04十億。這些票據是根據2022年9月15日的契約或契約發行的。該契約包括習慣契約,規定了某些違約事件,之後可以宣佈票據立即到期並付款,並規定了涉及公司的某些類型的破產或破產違約事件,之後票據將自動到期和支付。
21

目錄
ALNYLAm製藥公司。
簡明合併財務報表附註
(未經審計)
這些票據將於2027年9月15日到期,除非提前轉換、贖回或回購。票據的利率爲 1每年%的票據利息按半年度付息,分別於每年3月15日和9月15日預付,自2023年3月15日起。票據可由持票人在2027年6月15日或之後選擇轉換。在2027年6月15日之前,除非以下情況:(1)自2022年12月31日結束的每個日曆季度開始的日曆季度期間(僅在此日曆季度期間)如果我們的普通股最後報告的銷售價格至少爲 20個交易日,無論是否連續30連續交易日,每天的交易價格均大於或等於轉換價格的%,最後一個交易日爲上一日曆季度的最後一個交易日。13010五個營運部門:獵鷹創意集團、PDP、Sierra Parima、目的地運營和Falcon's Beyond Brands,所有這些板塊均爲可報告板塊。公司的首席營運決策者是執行主席和首席執行官,他們評估財務信息以做出營運決策、評估財務表現和分配資源。營運板塊基於產品線組織,對於我們的基於位置的娛樂板塊,根據地理位置組織。營運板塊的結果包括直接歸屬於板塊的成本,包括項目成本、工資和與工資有關的開支以及與業務板塊運營直接相關的間接費用。未分配的企業費用,包括高管、會計、財務、市場營銷、人力資源、法律和信息技術支持服務、審計、稅收企業法律開支的工資和相關福利,作爲未分配的企業開銷呈現,成爲報告板塊的總收入(虧損)和公司未經審計的彙總財務報表結果之間的調節項。連續的x個交易日後,緊接着的y個交易日內。票的投票權。 交易日轉換價值爲每1,000元債券本金的價格爲債券轉換日的普通股的最後報告銷售價格與債券的轉換比率的乘積的價值爲美元的 % 連續交易日期間(如有);因此,交易價格低於美元1,000元的債券不可轉換爲普通股。 票的投票權。 連續交易日期少於 98上市公司普通股最近報告的交易價格與票據轉換率的乘積的百分比;(3)如果我們要求任何或全部票據贖回;或(4)根據規定票據的契約發生特定公司事件時。我們將以現金、我們的普通股股份或現金和普通股股份的組合,根據我們的選擇,結算票據的任何轉換。
票據的轉換率最初爲每1000美元票面金額的3.4941股普通股,相當於約每股286.20 。票據的初始轉換價格相當於普通股每股約 35212.00 每股的報價。票據的初始轉換價格較普通股2022年9月12日最後報告的銷售價格溢價約每股。轉換率可能根據契約條款在特定情況下進行調整。
在2025年9月20日之前,我們可能不會贖回這些票據。我們可以選擇在2025年9月20日之後就票據的本金金額和已計息未支付的利息中的全部或部分以現金方式贖回。 100在2025年9月20日之後,如果我們的普通股最近報告的銷售價格至少達到百分之【】,我們可以選擇對票據的全部或部分進行贖回,包括已計息未支付的利息。 1301020在任何{days}個連續的交易日期間內,此期間的每張債券的每1000美元的票面金額的「交易價格」低於以贖回日前一天爲基準的交易日的通知日期計算的每張債券的票面金額的百分之{principal amount}%。30 在連續的交易日期間,不設立基金用於贖回這些票據,因此我們沒有必要定期贖回或購回這些票據。
如果我們經歷了《契約》中定義的根本變化,則在一定條件下,持有人可以要求我們按基本變化贖回價格用現金收回全部或部分票據。 100票據未滿足持有人轉換條件時,若在到期日期之前發生特定公司事件或我們發佈贖回通知,我們將爲選擇在此類公司事件中轉換其票據的持有人按預先定義的金額增加轉換率。這個條件並未在本季度滿足。
截至2024年9月30日和2023年12月31日,票據被分類爲長期負債,減去未攤銷的發行成本$11.3萬美元和14.2 百萬,在分別的簡明綜合資產負債表中。截至2024年9月30日和2023年12月31日,票據的估計公允價值分別約爲$1.19億美元和1.02十年和十二個月到期的票據,利用上述對象分別截至2024年9月30日和2023年12月31日的最後活躍交易價格每$100的金額確定(二級)。票據以面值發行,與發行有關的成本分攤到票據的合同期限內的利息費用上。截至2024年9月30日和2023年12月31日,票據的實際利率爲1%.
看漲式認購交易
2022年,關於初始票據的定價以及初始買方行使購買額外票據期權,我們進行了私下協商的封頂看漲交易,或稱爲封頂看漲交易(Capped Call Transactions)。封頂看漲交易最初覆蓋了作爲票據基礎的普通股份的股數,根據慣例防稀釋調整。封頂看漲交易的封頂價最初爲$424.00 相對於2024年2月21日紐交所公司普通股報價 100% 超過2022年9月12日普通股報告的最後交易價$一股,受封頂看漲交易條款下的某些調整的約束。212.00 每股$2022年9月12日普通股最後報告的銷售價格,以及根據封頂看漲交易條款的某些調整。
9. 未來版稅銷售相關責任
2020年4月,我們與BX Bodyguard Royalties L.P.(黑石集團的子公司)或黑石特許權使用費簽訂了購買和銷售協議或收購協議,根據該協議,黑石特許權使用費收購一定比例的應付特許權使用費或特許權使用費利息,最初定爲 50佔MDCO、其關聯公司或inclisiran(或品牌藥品Leqvio)和MDCO許可協議下任何其他許可產品的分許可持有人的淨銷售額的百分比,以及 75根據MDCO許可協議應付的商業里程碑付款的百分比,以及萬億.e購買的利息的特許權使用費利息。如果黑石特許權使用費在 2029 年 12 月 31 日之前沒有收到與特許權使用費利息相關的付款,金額至少等於美元1.00十億美元,黑石特許權使用費將獲得的特許權使用費利息 55% 從 2030 年 1 月 1 日開始。作爲出售購買權益的對價,黑石特許權使用費向我們支付了美元1.00十億。
22

目錄
ALNYLAm製藥公司。
簡明合併財務報表附註
(未經審計)
由於我們繼續參與並有義務償還BX Bodyguard Royalties L.P.,我們將從這筆交易的收益淨額減去了成交費用,在我們的簡明綜合資產負債表上記錄其爲債務。我們將根據MDCO許可協議收到的任何特許權使用費和商業里程碑作爲營業收入記錄在我們的簡明綜合利潤與損失表上。
爲了確定與未來版稅出售相關的負債攤銷,我們需要估計黑石版稅在購買協議期間的未來支付總額。在簽訂協議時確認的10億美元負債將按照協議期間的版稅和商業里程碑支付的總額計提爲利息費用。截至2024年9月30日及2023年12月31日,我們對這一利息費用的估計導致了相應的年度有效利率爲1.00,分別爲。這些估計包含會影響簽訂時確認金額以及未來期間將確認的利息費用的假設。 9%和8,分別。這些估計所涉及的假設將影響簽訂時確認金額以及將來期間認可的利息費用。
隨着支付給黑石的專利費,負債餘額將在購買協議的有效期內得到償還。償還的確切時間和金額可能會在每個報告期發生變化。Leqvio全球淨收入的顯著增加或減少將對與未來專利權銷售相關的負債、利息費用以及償還期限產生重大影響。我們將定期評估支付給黑石專利費的預期金額,如果這些支付的金額或時間與我們最初的估計存在重大差異,我們將前瞻性地調整與未來專利權銷售相關的負債攤銷和相關利息費用。
截至2024年9月30日和2023年12月31日,與未來版稅銷售有關的負債賬面價值爲$1.42億,扣除$9.3$400萬、$300萬和$500萬。1.38億的收盤成本,扣除$10.0百萬,分別。與未來版稅銷售有關的負債賬面價值截至2024年9月30日大致等於公允價值,並且基於我們對未來版稅和商業里程碑的當前估計,預計將支付給黑石版稅公司,這些被視爲三級輸入。
以下表格顯示了與未來版稅銷售相關的責任活動,以千爲單位:
2023年12月31日的賬面價值
$1,377,239 
確認的利息費用91,834 
付款(44,708)
2024年9月30日的賬面價值
$1,424,365 
10. 發展衍生責任
2020年8月,我們與BXLS V Bodyguard — PCP L.P. 和BXLS Family Investment Partnershies V — ESC L.P.(統稱爲黑石生命科學)簽訂了一項共同開發協議,稱爲融資協議,根據該協議,黑石生命科學將提供高達美元的資金150.0爲我們的兩個心臟代謝項目 vutrisiran 和 zilebesiran 的臨床開發提供了數百萬美元的資金。截至2024年9月30日,黑石集團已提供美元70.0百萬美元用於資助與 Helios-B 3 期臨床試驗相關的伏特利西蘭開發費用,以及 $26.0百萬美元用於資助 zilebesiran 2 期臨床試驗。此外, 黑石生命科學有權, 但沒有義務, 提供高達 $ 的資金54.0百萬美元用於與齊勒貝西蘭的3期臨床試驗相關的開發成本。黑石生命科學最終爲zilebesiran的3期臨床試驗提供的資金金額取決於我們實現規定的開發里程碑。在黑石生命科學與公司之間,我們繼續全權負責伏特利西蘭和齊勒貝西蘭的開發和商業化。
作爲黑石生命科學爲伏特利西蘭臨床開發費用提供資金的考慮因素,我們已同意向黑石生命科學支付一筆費用 1AMVUTTRA(vutrisiran)淨銷售額的特許權使用費百分比 10 年 期限從監管部門批准伏特利西蘭用於ATTR-心肌病後的首次商業銷售開始,以及最高的固定付款 2.5 他們的投資是他們的投資的倍數 兩年 在特定國家監管部門批准伏特利西蘭用於ATTR-心肌病的期限內,除非伏特利西蘭隨後在強制召回後退出市場。作爲黑石生命科學爲zilebesiran的第二階段臨床開發費用提供資金的對價,我們已同意向黑石生命科學支付最高的固定款項 3.25 他們第二階段投資的倍數是 四年 自zilebesiran 2期臨床試驗成功完成之日起,除非出現影響齊樂貝西蘭持續開發的某些監管事件。2023 年 9 月,我們宣佈了 zilebesiran KARDIA-1 2 期臨床試驗的積極結果,觸發了開發里程碑的實現84.5按等額支付給 Blackstone Life Sciences 的 16 萬英鎊,季度付款已超過 四年。作爲黑石生命科學爲zilebesiran的3期臨床開發費用提供資金的考慮因素,我們已同意向黑石生命科學支付不超過三期臨床開發費用的固定付款 4.5 他們第三階段投資的倍數是 四年 自特定國家監管部門批准zilebesiran之日起的一段時間,除非該產品隨後在強制召回後退出市場。
23

目錄
ALNYLAm製藥公司。
簡明合併財務報表附註
(未經審計)
根據融資協議,我們的支付義務將得到保障,除特定例外情況外,該保障將由我們在vutrisiran和zilebesiran知識產權上的安防-半導體利益以及我們的銀行帳戶所提供,這些資金存款將存入該帳戶。
我們和黑石生命科學各自有權在對方破產或類似訴訟事件發生時終止資金協議。我們和黑石生命科學可以分別終止整個資金協議,或者針對任一產品,在對方發生未經糾正的重大違約行爲,或因某產品出於某些患者健康和安全原因,或因在針對產品完成臨床試驗後,在指定的主要市場國家未獲得產品的監管批准。此外,黑石生命科學有權在發生影響我們支付協議下款項的某些事件或開發或商業化產品能力的事件,或者我們發生控制權變更時終止整個資金協議。黑石生命科學還可以在以下情況下終止資金協議,即聯合導向委員會決定終止完全某產品的開發項目,或者某產品未實現某些臨床終點,或者僅限於vutrisiran,我們開發或商業化vutrisiran的權利在指定的主要市場因涉嫌專利侵權而被禁止的情況下。在某些終止情況下,我們將有義務向黑石生命科學支付與從黑石生命科學收到的開發資金相等或倍數的金額,我們在某些情況下可能繼續有義務向黑石生命科學支付上述支付,或在AMVUTTRA情況下支付上述的授權金,如果我們在終止後獲得zilebesiran或vutrisiran針對具有心肌病的ATTR澱粉樣變病的監管批准。
根據ASC 815,我們將基金協議視爲衍生負債,按公允價值計量,記錄在我們的簡明合併資產負債表中的應計費用或其他負債中,具體取決於我們向黑石生命科學付款的時間。由於開發衍生負債重估引起的公允價值變動被記錄爲我們簡明合併損益表上的其他費用及綜合(損失)收入。
截至2024年9月30日,衍生負債被分類爲公允價值層次中的Level 3金融負債。估值方法包括某些不可觀察的Level 3關鍵輸入,包括(i)實現Blackstone Life Sciences支付里程碑的概率和時間,(ii)實現監管批准和向Blackstone Life Sciences支付的概率和時間,(iii)對AMVUTTRA淨銷售額上應支付的版稅金額和時間的估計,假設獲得ATTR澱粉樣蛋白病伴心肌病的監管批准,(iv)我們的借貸成本(11),及(v)Blackstone Life Sciences的借貸成本(6%).
以下表格顯示了與發展衍生責任相關的活動,以千爲單位:
2023年12月31日的賬面價值
$324,941 
根據資金協議收到的款項12,333 
根據資金協議支付的款項(15,844)
發展衍生負債公允價值變動100,499 
2024年9月30日的賬面價值
$421,929 
11. 基於股票的報酬
以下表格總結了包含在我們簡明合併利潤表的營業成本和費用中的股票報酬支出,以及包含在我們簡明合併股東權益(赤字)報表的額外資本公積金中的股票報酬費用:
 截至9月30日的三個月截至9月30日的九個月
(以千爲單位)2024202320242023
研發$19,794 $29,155 $87,124 $78,188 
銷售、一般及行政費用26,010 34,782 93,315 101,498 
共計股份獎勵支出
45,804 63,937 180,439 179,686 
資本化的股權補償成本
808 936 2,424 3,313 
總股權補償費用
$46,612 $64,873 $182,863 $182,999 

24

目錄
ALNYLAm製藥公司。
簡明合併財務報表附註
(未經審計)
12. 普通股每股淨(損失)收益
我們通過將淨(虧)利潤除以流通在外的普通股加權平均數來計算每股基本淨(虧)收益。我們通過將淨(虧)利潤除以普通股和需要稀釋的潛在普通股份的加權平均數來計算每股攤薄淨(虧)收益,這些潛在普通股份現已存在於報告期內。在攤薄淨(虧)收益每股的計算中,淨(虧)利潤會按照可轉換債務的利息費用被調整。潛在的普通股包括受限制股票單位解禁、行使股票期權(所得款項據以已用於根據庫藏股法回購未流通股份)以及在報告期內未流通的可轉債換股(使用按照轉換時方法計算的,假設將債務轉換爲普通股於最早公佈期間或於發行日期後)。由於潛在普通股的加入會使虧損期出現抵消效應,因此每股攤薄淨(虧)收益與每股基本淨(虧)收益相同。
以下表格列出了潛在的普通股份(在考慮庫存股或轉換後的方法之前)排除在每股普通股淨虧損計算之外,因爲它們的納入會導致稀釋效果。
截至2022年9月30日,
(以千爲單位)20242023
購買普通股票的期權,包括基於績效的股票期權5,388 1,301 
未獲授予的受限制股票單位,包括基於績效的受限制股票單位2,779 4 
可轉換債券3,616  
總費用11,783 1,305 
下表列出了基本和攤薄每股淨(虧損)收益的計算:
截至9月30日的三個月截至9月30日的九個月
2024年4月27日
2024202320242023
按報告的淨(虧損)收入
$(111,570)$147,753 $(194,394)$(302,372)
調整轉換債務利息的清除
 3,525   
用於稀釋每股收益的淨(虧損)收入
$(111,570)$151,278 $(194,394)$(302,372)
基本加權平均普通股份
128,590 125,220 127,159 124,667 
攤薄效應:
可轉換債券 3,616   
購買普通股的期權,包括基於績效的股票期權 2,134   
受限股單位,包括基於績效的受限股單位
 361   
員工股票購買計劃
 6   
攤薄加權平均普通股份
128,590 131,337 127,159 124,667 
每股普通股淨(損)收益 - 基本
$(0.87)$1.18 $(1.53)$(2.43)
每股普通股淨(損)收益 - 稀釋
$(0.87)$1.15 $(1.53)$(2.43)
13. 承諾和 contingencies
科技許可和其他承諾
我們已經從第三方獲得許可,以在我們的研究過程中以及我們可能開發的其他產品中使用特定的科技和信息。根據相關的許可或技術協議,我們需要在不同的協議期限內向許可方或許可方的被授權人進行一定的固定支付。這些協議期限中的許多與我們已經取得許可的基礎知識產權的剩餘生命週期一致。截至
25

目錄
ALNYLAm製藥公司。
簡明合併財務報表附註
(未經審計)
2024年9月30日,在未來五年內,根據現有許可協議進行的固定和可取消付款承諾並不重要。
法律事項
我們可能會不時捲入訴訟、仲裁或其他法律訴訟,包括以下描述的事項。我們可能會參與的索賠和法律訴訟包括對與我們的產品或產品候選品相關的專利的範圍、有效性或可執行性的質疑,以及我們對他人持有的專利範圍、有效性或可執行性的質疑。這些包括第三方聲稱我們侵犯其專利或違反與這些第三方許可或其他協議的索賠。任何此類法律訴訟的結果,不論其優勢如何,都存在不確定性。此外,訴訟和相關事項費用高昂,可能轉移我們管理層和其他資源的注意力,否則這些資源將從事其他活動。如果我們無法在任何此類法律訴訟中取得勝利,我們的業務、運營結果、流動性和財務狀況可能會受到不利影響。我們對法律費用的計提會確認這類費用在發生時。
專利侵權訴訟
2022年3月,我們在美國特拉華地區法院對輝瑞公司及其子公司Farmacia和Upjohn Co. LLC(統稱爲輝瑞公司)以及Moderna公司及其子公司ModernaTX公司和Moderna US公司(統稱爲Moderna公司)提起了單獨的訴訟,尋求賠償,因其在製造和銷售mRNA COVID-19疫苗中侵犯了美國專利第11,246,933號,或'933專利。該專利涉及公司的可生物降解的陽離子脂質,這是mRNA COVID-19疫苗成功的基礎。
我們尋求判決,認定輝瑞和moderna各自侵犯了‘933專利,並要求適當賠償侵權,但不低於法院判定的合理特許權費用,以彌補輝瑞和moderna對我們專利脂質的未經許可使用,同時支付法院裁定的利息和費用。正如所述,我們在已提起的訴訟中並未尋求禁令救濟。
2022年5月23日,moderna提交了一份部分駁回動議,聲稱根據第1498(a)條款提出了肯定的軍工股。我們於2022年5月27日作出回應,反對其動議,認爲moderna有重大的非政府銷售額,並且政府合同已於2022年4月結束。moderna於2022年6月13日作出回應,要求部分駁回針對第1498(a)條款下銷售索賠的動議。
2022年5月27日,輝瑞提交答辯,否認指控,並提出無效性和非侵權辯護。此外,輝瑞將BioNTech SE加入訴訟,並加入反訴,尋求裁決我們專利無效,並指控我們專利因專利濫用無效。我們認爲他們的辯護和反訴毫無根據,並於2022年6月10日回應,就我們主張的有效性以及他們的專利濫用主張的無根據性提出實質性論據。
2022年7月12日,我們對輝瑞和moderna分別提起了一項額外的訴訟,尋求賠償美國專利第11,382,979號(簡稱『979專利』)的侵權,因爲輝瑞和moderna在製造和銷售他們的mRNA COVID-19疫苗中侵犯了該專利。各方同意合併 兩個 專利訴訟,分別針對moderna和輝瑞/biontech。 之一 訴訟中的專利,分別針對moderna和輝瑞/biontech。
2023年2月8日,我們收到了美國專利局的通知,稱第三項專利將於2023年2月28日授予,即美國專利號11,590,229,我們認爲輝瑞和moderna的COVID-19疫苗也侵犯了該專利。 2023年2月15日,我們向法院提出動議,將該專利加入針對輝瑞和moderna的現有案件,2023年4月26日,法院進行了聽證會,並拒絕了moderna針對根據第1498(a)條款銷售索賠的部分駁回動議,我們的動議將‘229專利添加到當時的訴訟中,以及moderna提出的補充輝瑞在我方案件中提出的某些無效理由的動議以補充moderna先前提出的無效理由。
2023年5月26日,我們在特拉華州對輝瑞和moderna提起了額外的訴訟,尋求侵犯‘229專利的賠償。除了這項專利外,我們還聲稱輝瑞和moderna侵犯了美國專利號11,633,479,即‘479專利,和11,633,480,以及針對輝瑞的美國專利號11,612,657。
2023 年 8 月 9 日,美國特拉華特區地方法院舉行了馬克曼聽證會,以考慮 933年和979年專利中使用的有爭議的術語。2023 年 8 月 21 日,法院發佈了一項命令,解釋 條款,並將對第三個任期的裁決推遲到2024年1月4日舉行的證據聽證會之前,最終裁決推遲到2024年7月12日舉行的另一次證據聽證會的結果,隨後於2024年9月19日舉行了額外的證據聽證會,當時法院對最終索賠期限的解釋很狹窄。根據 2023 年 8 月 21 日的命令,我們和 Moderna 共同同意作出不侵權的最終判決 我們的專利,法院於2023年8月30日作出了這樣的判決。2023年9月7日,我們在針對Moderna的首次訴訟中向聯邦巡迴上訴法院對索賠解釋裁決提出上訴。這個
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ALNYLAm製藥公司。
簡明合併財務報表附註
(未經審計)
認領施工規則最初並未影響 之一 2023年5月26日提起訴訟起訴moderna的專利中,經過2024年8月15日舉行的聽證會,2024年9月10日,法院作出與之前一起案件相同方式的裁決,2024年10月2日,我們和moderna共同同意就‘479專利的無侵權判決達成最終裁決,並保留所有上訴權利。 2024年10月16日,moderna提出動議,尋求從我們同意第一起案件中的無侵權判決至第二案件中的無侵權判決的時間內,即從大約2023年9月至2024年10月期間,他們所支出費用的賠償。 我們的回覆截止日期爲2024年11月6日。 I鑑於此事處於早期階段,尚未確定因此事而產生的任何損失(若有),可能性以及任何此類損失的數額或區間是否可以合理估算。
本基金尋求於東歐地區註冊的主要權益關聯發行人的長期升值投資。兩個 針對輝瑞的單獨訴訟仍在進行中,2023年9月,我們和輝瑞同意將2022年和2023年的訴訟合併 之一 案件定於2025年7月7日進行審判。
2024年7月12日,Acuitas Therapeutics, Inc.或Acuitas在美國特拉華州地區法院對我們提起了一項宣判訴訟,尋求對我們在訴訟中針對輝瑞/BioNTech和moderna的專利中添加某些Acuitas僱員爲共同發明人的判決。2024年9月19日,我們提出了一項駁回動議,稱Acuitas無權起訴並未能陳述可獲得救濟的主張。法院尚未對我們的駁回動議做出裁決。
賠償責任
就與公司簽訂的許可協議相關的事項,爲取得知識產權,我們可能需要爲與該等協議下授權的知識產權有關的某些損害賠償這些公司。根據這些協議,我們可能需要支付與許可協議或相關知識產權有關的訴訟費用,包括與受許可知識產權有關的特定訴訟的費用。我們也是許多與業務常規進行的協議的一方,這些協議包含典型的條款,義務我們在發生某些事件時對這些協議的其他方進行賠償,包括訴訟或其他法律程序。此外,我們已同意賠償我們的高管和董事們在與威脅、進行中或已完成的訴訟程序有關的費用、判決、罰款、處罰稅和解決金額,其中高管或董事作爲訴訟程序中的當事方是、曾是或將是,因其作爲高管或董事的身份,或由於高管或董事在履行這種職能時採取的任何行動而受到,受到某些限制。這些賠償費用列入銷售、一般和管理費用。
我們在任何此類補償條款下的最大潛在未來責任是不確定的。我們已確定所有此類補償條款下潛在責任的估計累計公允價值是最低的,並截至2024年9月30日尚未記錄與此類補償條款有關的任何責任。
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項目2. 管理討論與分析財務狀況和業績
以下討論包含管理層對我們的財務狀況和經營業績的討論與分析,並應與我們的未經審計的簡明綜合財務基本報表以及相關附註一起閱讀,這些內容在本季度報告表格10-Q的其他地方包含。
概述
我們是一家全球商業階段的生物製藥公司,開發基於RNA干擾的新型治療方法。RNA干擾是細胞內的一種自然生物途徑,用於序列特異性沉默和調控基因表達。通過利用RNA干擾途徑,我們開發了一類新型創新藥物,稱爲RNA干擾治療。RNA干擾治療由小干擾RNA(siRNA)組成,通過有效沉默編碼導致疾病起因或途徑中的蛋白質的信使RNA(mRNA),從而防止其合成。我們認爲這是一種具有革命性潛力的方法,可以改變罕見和普遍疾病患者的護理方式。迄今爲止,我們推動這一革命性方法的努力已經獲得了五種第一類RNA干擾藥物的批准,分別爲AMVUTTRA® (vutrisiran),ONPATTRO® (patisiran),GIVLAARI® (givosiran),OXLUMO® 拉馬西蘭(lumasiran)和萊慶(Leqvio)® 包括施維諾(inclisiran)。
我們的研發策略是針對在人類疾病的原因或通路中已被證實的基因。我們利用N-乙酰半乳糖胺(GalNAc)共軛方法或脂質納米粒子(LNP)實現siRNA的肝臟傳遞。針對中樞神經系統(CNS)和眼睛(眼部傳遞)的傳遞,我們正在利用基於十六烷基(C16)基團的另類共軛方法作爲親脂性配體。我們還在推進siRNA對心臟、骨骼肌肉和脂肪組織的傳遞方法。我們的重點是在臨床上有高度未滿足需求、有基因驗證的靶點、一期臨床試驗中評估臨床活性的早期生物標誌物,以及明確的藥物開發、監管批准、病患獲得和商業化路徑。
在2021年初,我們推出了我們的策略,重點是計劃在2025年底轉型爲一家頂尖生物科技公司。 賽諾菲安萬特P5x25 策略,側重於我們計劃在2025年底之前轉型成爲一家頂級生物科技公司。隨着 賽諾菲安萬特P5x25,我們旨在通過可持續創新爲全球患者提供轉變性稀有病、特殊病和部分常見疾病的藥物,同時實現卓越的財務表現。
我們目前擁有五種市場產品和十餘個臨床項目,包括幾個處於晚期開發階段,涵蓋罕見病、特殊疾病和部分常見適應症。
AMVUTTRA已在美國獲批用於治療遺傳性甲狀腺激素轉運前體介導的澱粉樣蛋白沉積症,或稱hATTR澱粉樣蛋白沉積症,伴有多發性神經病的成人,在歐洲聯盟(EU)和英國(UK)用於治療成人患有第1或第2期多發性神經病的hATTR澱粉樣蛋白沉積症,在日本用於治療轉運前體蛋白(TTR)型家族性澱粉樣蛋白沉積症伴有多發性神經病,以及在其他多個國家。 其他地區的監管審查仍在進行中。 我們報告了vutrisiran(AMVUTTRA的通用名)用於治療具有心肌病的ATTR澱粉樣蛋白沉積症的HELIOS-b臨床試驗的積極上市結果,並宣佈我們計劃在今年晚些時候繼續進行全球監管備案,以尋求將AMVUTTRA批准爲ATTR澱粉樣蛋白沉積症伴有心肌病的潛在治療方案。 在2024年6月,我們報告了HELIOS-b臨床試驗的詳細結果。2024年8月和9月,我們宣佈報告了HELIOS-b臨床試驗的詳細結果。2024年10月9日,我們宣佈已向美國食品藥物管理局(FDA)提交了一份補充新藥申請(sNDA),並使用了一張優先審閱券,並於2024年10月16日宣佈已向歐洲藥品管理局(EMA)提交了II類變更申請。
ONPATTRO已在美國獲批用於治療成人hATTR澱粉樣變性的多發性神經病,也已在歐盟獲批用於治療具有第1或第2期多發性神經病的成人hATTR澱粉樣變性患者,日本獲批用於治療帶有多發性神經病的TTR型家族性澱粉樣變性,以及在多個其他國家也獲批。Patisiran (ONPATTRO的通用名稱)正接受巴西衛生監管局(ANVISA)審查,用於治療具有心肌病的ATTR澱粉樣變性。
GIVLAARI已獲得美國批准,用於治療成人急性肝性porphyria(AHP),在歐盟用於治療成人和12歲及以上青少年的AHP,在其他幾個國家也獲得批准。givosiran(GIVLAARI的通用名稱)的監管申請在其他地區仍在等待或計劃於2024年及以後進行。
OXLUMO已在美國獲批,用於治療一型原發性高草酸尿症(PH1),降低兒童和成人患者的尿液和血漿草酸鹽水平,在歐盟和英國也已批准用於各年齡段PH1的治療。OXLUMO還在其他幾個國家獲得了批准,並且針對lumasiran(OXLUMO的通用名稱)的監管申報已在2024年及以後的時間段內在其他領土中進行中或計劃中。
Leqvio(inclisiran),我們的第五個產品,由我們的合作伙伴諾華製藥(Novartis AG)開發和商業化,並已獲得歐洲委員會(EC)批准,用於治療成人高膽固醇血癥或混合脂蛋白血癥,以及獲得FDA批准,作爲飲食的補充和最大耐受的他汀治療成年人的治療具有雜合子家族性高膽固醇血癥(HeFH)或臨床動脈粥樣硬化心血管病(ASCVD)的患者,需要降低低密度脂蛋白膽固醇(LDL-C)水平。2023年7月,FDA
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Leqvio已獲批准擴大適應症,包括治療LDL-C偏高且心臟病風險增加的成年人。Leqvio還在中國和日本獲得批准,並截至2024年9月底,Leqvio已在100多個國家註冊,並在78個國家商業上市。
除了我們銷售的產品外,作爲我們的一部分 Alnylam P5x25 戰略,我們有多種未來增長驅動力,包括開發治療流行疾病的變革性藥物。除Leqvio外,我們還在推進zilebesiran,這是一種用於治療高血壓的研究性皮下給藥RNAi療法,靶向血管緊張素原。2023年,我們與F. Hoffmann-La Roche Ltd.和Genentech, Inc.或統稱爲羅氏簽訂了合作和許可協議,即《羅氏合作與許可協議》,根據該協議,我們建立了全球戰略合作,共同開發和商業化zilebesiran。2024 年 3 月,我們報告了 KARDIA-2 臨床試驗的積極結果,該試驗旨在評估每半年作爲伴隨療法對血壓未通過標準護理抗高血壓藥物充分控制的患者的安全性和有效性。2024 年 4 月,我們在 KARDIA-3 臨床試驗中爲第一位患者給藥,該試驗旨在評估齊樂貝西蘭作爲附加療法對儘管使用兩到四種標準護理抗高血壓藥物進行治療但仍具有高心血管風險和高血壓不受控制的成年患者的療效和安全性。
我們還在推進mivelsiran(前稱ALN-APP),這是一種研究性RNAi治療藥物,針對阿爾茨海默病和腦部澱粉樣前體蛋白進行開發。2024年10月,我們宣佈了mivelsiran在早髮型阿爾茨海默病患者中多劑量部分的1期臨床試驗的積極中期結果。2024年7月,我們在腦部澱粉樣前體蛋白患者中啓動了mivelsiran的CAPPRicorn-1 2期臨床試驗的給藥。
我們有進展中的額外晚期調查項目,朝着潛在商業化的方向發展,包括適度治療血友病的fitusiran項目,該項目由我們的合作伙伴賽諾菲安萬特公司(即賽諾飛)推進,已向FDA提交了NDA,目標行動日期爲2025年3月28日,以及治療補體介導疾病的cemdisiran項目,我們的合作伙伴再生元製藥公司正在與pozelimab組合進行第3期臨床試驗,用於重症肌無力和地理性萎縮,並作爲單藥療法用於早發性夜間血紅蛋白尿的第3期臨床試驗。
爲了進一步支持我們的 Alnylam P5x25 戰略,鑑於我們不斷變化的風險狀況,我們仍然專注於全球基礎設施的持續發展,包括關鍵目標,例如優化我們的全球結構以在關鍵市場執行,提高符合我們價值觀的業績,以及繼續加強我們的文化。我們將繼續建立我們的全球合規計劃,以推動其發展和改進。我們的合規計劃以我們的全球商業行爲和道德準則爲基礎,旨在使我們的員工和與我們合作的人員能夠根據我們的價值觀和適用的法律法規執行我們的戰略,並降低風險。我們的計劃和相關控制措施由風險評估和監測、政策、程序和指導、培訓和溝通、專用資源以及支持第三方關係、調查和補救等活動的系統和流程等組成部分;我們的計劃和相關控制措施旨在加強我們在全球運營中的業務流程、結構和控制,並增強道德決策。
基於我們在RNAi治療領域的專業知識和廣泛的知識產權,我們與領先的藥品和生命科學公司建立了合作關係,以支持我們的開發和商業化工作,包括羅氏、再生元、賽諾菲安萬特和諾華(後者在2020年收購了我們的合作伙伴The Medicines Company,簡稱MDCO)。
自2002年開始經營以來,我們已經遭受了巨大的損失,截至2024年9月30日,累計赤字達到72億美元。從歷史上看,我們主要由於研發活動成本、知識產權的獲取、申請和擴展,以及銷售、總務和行政成本而出現虧損。由於計劃中用於研究平台、藥物研發項目(包括臨床試驗和製造成本)、晚期臨床和商業能力的構建,包括全球商業運營、專利組合的管理和持續成長、合作伙伴關係和一般公司活動的研發活動支出,我們可能會發生額外的營運虧損。在未來幾年,隨着我們擴大努力去發現、發展和商業化RNAi治療方案,我們將需要大量資源,並計劃在2025年底實現財務自給自足。我們預計未來我們的營運業績將繼續波動,因此,不應依賴週期性比較作爲未來期間結果的預測。
截至2024年9月30日,我們目前專注於多個治療領域的項目,並從四種已商業化產品ONPATTRO,AMVUTTRA,GIVLAARI和OXLUMO在美國和歐洲主要產生全球產品收入。然而,我們正在進行的研發和監管工作可能並不成功,我們可能無法開始銷售任何其他產品和/或成功擴展現有商業化產品的標籤或市場並銷售我們未來的所有其他批准產品。近年來我們總收入的重要部分來自與羅氏、再生元和諾華合作的合作收入。除了來自商業化產品的商業銷售和未來潛在產品的銷售收入外,我們預計未來數年的潛在資金來源將繼續部分來自現有和新的戰略合作伙伴關係。
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合作內容。這些合作內容包括或將來可能包括許可和其他費用,資助的研發,里程碑付款,以及我們的許可方提供的產品銷售版稅,其中包括由我們的合作伙伴諾華銷售Leqvio的版稅,以及通過出售股權或債務獲得的收益。
迄今爲止,我們的研究和開發費用與AV-101的開發有關。研究和開發費用按照發生的原則確認,並將在收到將用於研究和開發的貨物或服務之前支付的款項資本化,直至收到這些貨物或服務。
自我們成立以來,我們主要專注於藥物發現和開發項目。研發費用佔我們總營業費用的相當大部分,這主要體現在我們廣泛的臨床開發項目管線上,包括多個處於後期開發階段的項目。
我們的產品管道
我們的廣泛管線包括五種已獲批准的產品和多種晚期和早期調查性RNAi治療藥物,滿足了多個疾病領域的未滿足需求,並涵蓋了罕見病、特殊病和少數常見疾病的指標。我們將在下文更詳細地介紹我們的商業和臨床管線。下文描述的調查性治療藥物處於臨床開發的不同階段,關於這些治療藥物的科學信息是初步的和調查性的。這些調查性治療藥物尚未獲得FDA、EMA或任何其他衛生管理機構的批准,對於這些調查性治療藥物的安全性或有效性不能得出任何結論,也不應該得出。
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以下表格展示了截至2024年10月31日的商業產品以及後期和早期階段的開發項目。

ALNY Pipeline_2024_10Q-K_ProductNames_3.jpg

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目錄
在2024年第三季度及近期,我們報告了以下來自我們商業批准產品和後期臨床計劃的更新:
商業用途
總轉換比率:ONPATTRO和AMVUTTRA
2024年第三季度,ONPATTRO和AMVUTTRA的全球淨產品收入分別爲5030萬美元和25860萬美元。
稀有總量:GIVLAARI和OXLUMO
我們在2024年第三季度分別實現了全球貨幣的GIVLAARI和OXLUMO淨產品收入分別爲7100萬美元和4020萬美元。
臨床後期開發階段
我們使用優先審評券向FDA提交了一個sNDA,同時向EMA提交了一個II型變更,用於對付帶心肌病的ATTR澱粉樣變性進行治療的vutrisiran。
我們宣佈了米維司蘭在阿爾茨海默病患者中進行的1期多劑量研究的初步積極結果。
存在風險,即任何藥物發現或開發項目由於各種原因可能無法產生營業收入,包括我們可能無法充分證明產品候選的安全性和有效性,或者獲得監管機構批准或所需的標籤。 此外,對於任何新的藥物發現領域(包括RNAi),存在特定的不確定性。 ONPATTRO、AMVUTTRA、GIVLAARI、OXLUMO或我們開發的任何其他產品候選的成功性高度不確定。 由於開發藥物涉及許多風險,我們無法合理估計或了解完成任何潛在產品候選或適應症的開發所需努力的性質、時間和估算成本,或者從任何獲批產品或適應症開始產生資金淨流入的時間,如果有的話。 未能及時完成任何潛在產品的開發任何階段或在擴大適應症上成功推出、推廣和銷售任何商業上獲批的產品可能對我們的運營、財務狀況和流動性產生重大不利影響。 在規定時間內完成我們的研發計劃或完全完成這些計劃以及未能這樣做的潛在後果的一些風險和不確定性討論,詳見下文第II部分,第1A項,標題爲「風險因素」。
戰略合作
我們的業務策略是開發和商業化一系列RNAi治療產品,針對改變性罕見病、專科和一些常見疾病。作爲這一策略的一部分,我們已經達成,並可能在將來達成額外的合作和許可協議,以獲得推進我們的RNAi治療項目所需的資源、能力和資金。
以下是我們一些重要合作的簡要描述。
羅氏公司2023年7月,我們與羅氏達成了合作與許可協議,根據協議,我們與羅氏建立了全球戰略合作,共同開發含有西力比賽的藥品。根據羅氏合作與許可協議,我們授予羅氏(i)在全球開發西力比賽和在美國商業化西力比賽的協同獨家權利,(ii)在美國以外獨家商業化西力比賽的獨家權利,以及(iii)在美國以外製造西力比賽以用於西力比賽的開發和商業化的非獨家權利。羅氏支付了31000萬美元的前期款項。2024年4月,我們在KARDIA-3第2期臨床試驗中首位患者服用西力比賽劑量達到了開發里程碑,並收到了羅氏6500萬美元的開發里程碑款項。此外,我們有資格根據特定開發、監管和銷售里程碑的達成而最多獲得額外的24.5億美元的有條件支付。我們對全球推動支持西力比賽監管批准開發活動產生的開發成本負責40%,而羅氏負責剩餘60%。我們與羅氏在支持西力比賽在美國獲得監管批准的開發活動方面均分享平等(50/50)的所有相關成本。在獲得監管批准後,羅氏將獨自承擔在美國以外商業化西力比賽所產生的成本,並根據西力比賽在美國以外的淨銷售額支付我們基於各國的分層低兩位數的版稅。我們與羅氏將平等分享(50/50)西力比賽在美國的利潤和損失(包括商業化成本)。
瑞金恩公司。 2019年4月,我們與瑞金恩公司達成全球戰略合作,共同發現、開發和商業化針對眼部和中樞神經系統以及少數肝臟表達的治療靶點的RNAi治療藥物。我們稱之爲瑞金恩合作。瑞金恩合作由一份大師協議管理,稱爲瑞金恩大師協議,於2019年5月生效。
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根據Regeneron合作協議的條款,我們與Regeneron獨家合作,爲眼部和中樞神經系統疾病的RNAi治療方案進行發現,首次研究期長達七年,我們稱之爲初始研究期。Regeneron有權選擇支付30000萬美元的研究期延長費,將初始研究期延長五年。Regeneron合作還涵蓋了旨在靶向肝臟基因表達的一系列RNAi治療項目。我們保留了全球所有未合作的肝臟定向臨床和臨床前管線項目的廣泛全球權益。
Regeneron領導開發和商業化所有目標眼部疾病的項目(受到有限的例外),根據許可協議的條款,我們有權獲得某些潛在的里程碑和版稅支付,各方已經就協議形式達成一致意見。我們和Regeneron交替領導中樞神經系統和肝臟項目,主導方保留全球開發和商業責任。
2019年8月,關於Regeneron主協議的事宜,我們與Regeneron簽署了(i)一份涵蓋繼續開發我們的C5 siRNA cemdisiran的合作協議,目前已用於治療C5互補介導的疾病,作爲單一療法,或稱爲C5合作協議;以及(ii)一項許可協議,用於評估抗C5抗體-siRNA組合對於C5互補介導的疾病的效果,包括評估Regeneron的pozelimab和cemdisiran的組合,或稱爲C5許可協議。2022年11月,Regeneron行使了其在C5合作協議下選擇退出進一步開發和商業化單一療法cemdisiran的權利,此時我們成爲開發和商業化C5 siRNA cemdisiran單一療法的唯一責任人,而Regeneron不再分擔任何單一療法項目的成本。Regeneron仍有資格根據cemdisiran單一療法的淨銷售額獲得分層的兩位數的版稅。
2024年6月,我們簽署了一份經修訂和重籤的C5許可協議(以下簡稱「修訂後的C5許可協議」),終止了C5 Co-Co合作協議,並授予再生元公司全球茨地西蘭的單藥治療許可,以及與抗C5抗體結合使用的茨地西蘭的許可。通過修訂後的C5許可協議,再生元公司現在全權負責茨地西蘭作爲單藥治療以及與抗C5抗體結合使用的開發、製造和商業化。再生元公司向我們提供了1000萬美元的預付款,並將在茨地西蘭作爲單藥治療獲得監管批准時收到特定的里程碑付款,以及根據淨銷售額進行分階段的兩位數折讓。修訂後的C5許可協議並未改變我們在茨地西蘭作爲組合產品的一部分時獲得低兩位數折讓和最高爲32500萬美元的商業里程碑款項的權利。
2024年5月,Regeneron通知我們決定選擇退出繼續共同開發mivelsiran,這是一種用於治療遺傳性CAA和常染色體顯性阿爾茨海默病的調查性RNAi治療藥物,根據我們與mivelsiran的合作協議,關於對mivelsiran的開發,全球性商業化權利則完全歸我們所有。因爲Regeneron選擇退出,我們現在負責mivelsiran在所有適應症的開發和商業化成本,包括我們正在進行的第1期計劃以外的部分。Regeneron將不再與我們分享mivelsiran銷售所帶來的潛在未來利潤,儘管我們仍需根據mivelsiran的合作協議對Regeneron負擔一定的財務義務。我們將繼續與Regeneron推進多個其他項目。
賽諾菲安萬特。 2014年,我們與賽諾菲形成了廣泛的戰略聯盟。2018年1月,我們與賽諾菲修改了2014年的合作協議,並簽署了獨家許可協議,稱爲獨家TTR許可協議,在此協議下,我們擁有進一步全球發展和商業化所有TTR產品的獨家權利,包括ONPATTRO、AMVUTTRA和任何備用產品,以及ALN-AT3全球許可條款,即AT3許可條款,根據該協議,賽諾菲擁有進一步全球發展和商業化fitusiran和任何備用產品的獨家權利。根據獨家TTR許可協議,賽諾菲有資格獲得(i)根據ONPATTRO在不包括美國、加拿大和西歐地區的年度淨銷售額,最高達25%逐漸增加的版稅,前提是ONPATTRO在日本的年度淨銷售額的版稅從獨家TTR許可協議生效日起設定爲25%,以及(ii)根據AMVUTTRA的全球年度淨銷售額,15%至30%的分級版稅。2019年4月,我們和賽諾菲同意進一步修改2014年的賽諾菲合作協議,結束研究和選擇階段,修訂和重申AT3許可條款以修改某些業務條款。fitusiran的重要合作條款保持不變。根據修改和重新訂立的AT3許可條款,根據賽諾菲、其關聯公司及其被許可人的全球fitusiran年度淨銷售額,我們有資格獲得15%至30%的分級版稅。
諾華製藥。 2013年2月,我們與MDCO(於2020年1月被諾華製藥收購)簽署了一項獨家全球許可協議,根據該協議,MDCO獲得了開發、生產和商業化RNai治療藥物的權利,以治療高膽固醇血癥和其他人類疾病,包括Leqvio。
我們還簽訂了許可協議,以獲取RNAi領域的知識產權。此外,由於RNAi治療藥物的傳遞歷來是我們研究活動的重要目標,我們已與其他公司和學術機構簽訂了各種合作和許可安排,以獲取傳遞技術,包括各種LNP傳遞技術,並且我們將來可能會簽訂此類協議以獲得產品或技術。
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關鍵會計政策和估計
我們的關鍵會計政策在我們於2024年2月15日向SEC提交的截至2023年12月31日的年度10-K表格的「管理層對財務狀況和經營結果的討論與分析」部分中有所描述。自這個財政年度開始以來,我們的關鍵會計政策沒有發生重大變化。
經營結果
以下數據總結了我們的運營結果:
 截至9月30日的三個月截至9月30日的九個月
(以千計,百分比除外)20242023$ Change% 變化20242023$ Change% 變化
總收入$500,919 $750,530 $(249,611)(33)%$1,655,077 $1,388,574 $266,503 19 %
運營成本和支出
$577,824 $536,663 $41,161 %$1,726,803 $1,554,345 $172,458 11 %
運營收入(虧損)$(76,905)$213,867 $(290,772)(136)%$(71,726)$(165,771)$94,045 (57)%
淨(虧損)收入$(111,570)$147,753 $(259,323)(176)%$(194,394)$(302,372)$107,978 (36)%
經營業績討論
收入
總收入包括以下內容:
 截至9月30日的三個月截至9月30日的九個月
(以千計,百分比除外)20242023$ Change% 變化20242023$ Change% 變化
產品淨收入$420,146 $313,153 $106,993 34 %$1,195,397 $895,186 $300,211 34 %
合作淨收入
57,387 427,472 (370,085)(87)%403,273 469,778 (66,505)(14)%
特許權使用費收入23,386 9,905 13,481 136 %56,407 23,610 32,797 139 %
總計$500,919 $750,530 $(249,611)(33)%$1,655,077 $1,388,574 $266,503 19 %
34

目錄
淨產品收入
淨產品收入包括以下內容,按產品和地域板塊劃分:
截至9月30日的三個月截至9月30日的九個月
(以千美元爲單位,除百分比外)20242023$ 變化百分比變動20242023$ 變化百分比變動
ONPATTRO
美國$16,207 $21,869 $(5,662)(26)%$54,858 $77,246 $(22,388)(29)%
歐洲24,327 50,371 (26,044)(52)%106,091 166,442 (60,351)(36)%
其餘地區9,759 9,349 410 %35,805 31,852 3,953 12 %
總費用50,293 81,589 (31,296)(38)%196,754 275,540 (78,786)(29)%
AMVUTTRA
美國168,658 113,508 55,150 49 %447,359 288,990 158,369 55 %
歐洲65,140 19,417 45,723 235 %165,633 40,590 125,043 308 %
其餘地區24,792 15,755 9,037 57 %70,948 53,004 17,944 34 %
總費用258,590 148,680 109,910 74 %683,940 382,584 301,356 79 %
GIVLAARI
美國40,372 37,009 3,363 %120,328 102,496 17,832 17 %
歐洲16,281 12,430 3,851 31 %47,910 40,952 6,958 17 %
其餘地區14,390 4,709 9,681 206 %22,988 16,505 6,483 39 %
總費用71,043 54,148 16,895 31 %191,226 159,953 31,273 20 %
OXLUMO
美國14,933 9,713 5,220 54 %44,009 27,564 16,445 60 %
歐洲19,977 15,086 4,891 32 %61,907 40,611 21,296 52 %
其餘地區5,310 3,937 1,373 35 %17,561 8,934 8,627 97 %
總費用40,220 28,736 11,484 40 %123,477 77,109 46,368 60 %
總淨產品收入$420,146 $313,153 $106,993 34 %$1,195,397 $895,186 $300,211 34 %
2024年9月30日結束的三個月和九個月內,與2023年同期相比,淨產品收入增加,因AMVUTTRA增長推動增加的患者需求,部分抵消由於患者轉換至AMVUTTRA,以及GIVLAARI和OXLUMO療法患者增加而導致的ONPATTRO減少。
合作和版稅的淨營業收入
合作收入和版稅收入中包括以下內容:
 截至9月30日的三個月截至9月30日的九個月
(以千美元爲單位,除百分比外)20242023$ 變化百分比變動20242023$ 變化百分比變動
羅氏公司
$16,289 $311,328 $(295,039)(95)%$107,475 $311,328 $(203,853)(65)%
再生元製藥公司37,948 80,254 (42,306)(53)%272,141 97,407 174,734 179 %
諾華製藥2,936 18,381 (15,445)(84)%19,756 41,941 (22,185)(53)%
其他214 17,509 (17,295)(99)%3,901 19,102 (15,201)(80)%
合作伙伴的總淨營業收入
$57,387 $427,472 $(370,085)(87)%$403,273 $469,778 $(66,505)(14)%
版稅收入
$23,386 $9,905 $13,481 136 %$56,407 $23,610 $32,797 139 %
35

目錄
2024年9月30日結束的三個月和九個月以及2023年同期相比,合作收入減少,主要原因是:
由於在2023年第三季度將許可證轉讓給羅氏公司,根據我們與羅氏公司的合作協議確認的營業收入爲31000萬美元。
由於在2023年第三季度由於Regeneron合作伙伴關係下對累計抓捕調整$6500萬的營業收入確認,從未成年分子mivelsiran(前ALN-APP)在早期臨床開發中達到某些標準賺得的$10000萬里程碑。
部分抵消:
根據我們於2024年6月修改的與Regeneron合作協議,授予Regeneron獨家開發、製造和商業化cemdisiran作爲單獨療法的專利許可,並根據我們與Roche合作在2024年9月30日結束的九個月中向zilebesiran KARDIA-3臨床試驗首位患者投藥而承認6500萬美元的營業收入。
在2024年9月30日結束的三個月和九個月內,與2023年同期相比,由於合作伙伴諾華(Novartis)從全球力凱歐(Leqvio)淨銷售額中賺取的版稅收入增加,導致營業收入和版稅率增加。
我們合併的合作淨營業收入和版稅收入的確認取決於多種因素,包括合作伙伴報銷的工作水平,根據我們的合作協議實現的里程碑,以及與Leqvio銷售相關的版稅。因此,與2023年相比,2024年從合作和版稅收入中確認的淨收入可能會有所變化。
營銷及一般管理費用
運營成本和費用包括以下內容:
 截至9月30日的三個月截至9月30日的九個月
(以千計,百分比除外)20242023$ Change% 變化20242023$ Change% 變化
售出商品的成本$81,980 $79,473 $2,507 %$203,864 $196,241 $7,623 %
銷售成本佔淨產品收入的百分比19.5 %25.4 %17.1 %21.9 %
合作成本和特許權使用費3,925 4,836 (911)(19)%16,689 28,307 (11,618)(41)%
研究和開發270,926 253,179 17,747 %826,063 732,274 93,789 13 %
銷售、一般和管理
220,993 199,175 21,818 11 %680,187 597,523 82,664 14 %
總計$577,824 $536,663 $41,161 %$1,726,803 $1,554,345 $172,458 11 %
售出商品的成本
營業成本佔淨產品收入比例在2024年9月30日結束的三個月和九個月內與2023年同期相比有所下降,主要是因爲2023年由於取消的製造業承諾和由於ONPATTRO庫存的減值而產生的較高成本,這部分庫存是爲未來需求製造的,與使用Patisiran治療具有心臟肌病的ATTR澱粉樣變患者相關。針對這些患者,我們在美國沒有獲得監管批准。這些下降部分地被AMVUTTRA淨銷售的更高成交量和版稅率所抵消。
除去2023年與取消的製造業承諾和ONPATTRO的減值有關的一次性事件,我們預計我們的營業成本佔淨產品收入的比例將在2024年增加,與2023年相比,這是由成交量和AMVUTTRA的淨銷售所需支付的版稅費率的增加驅動的。
合作與版稅的成本
截至2024年9月30日的三個月和九個月,與2023年同期相比,合作和版稅成本減少主要是由於我們的合作伙伴轉向獨立生產材料,需求減少GalNAc材料
我們預計,在2024年,與2023年相比,合作成本和版稅將繼續下降,因爲我們的合作伙伴正在過渡到獨立生產GalNAc,並由於第三方知識產權許可的到期而減少應付的版稅。
36

目錄
研發 
研究和開發支出包括以下內容:
截至9月30日的三個月截至9月30日的九個月
(以千美元爲單位,除百分比外)20242023$ 變化百分比變動20242023$ 變化百分比變動
臨床研究和外部服務$134,880 $112,558 $22,322 20 %$379,886 $333,853 $46,033 14 %
補償和相關75,316 68,112 7,204 11 %239,287 197,539 41,748 21 %
佔地面積和所有其他成本40,936 43,354 (2,418)(6)%119,766 122,694 (2,928)(2)%
以股票爲基礎的報酬計劃19,794 29,155 (9,361)(32)%87,124 78,188 8,936 11 %
總費用$270,926 $253,179 $17,747 %$826,063 $732,274 $93,789 13 %
截至2024年9月30日止三個月和九個月的研發費用增加與2023年同期相比,主要原因如下:
由於第2階段活動增加,主要與KARDIA-3試驗中的zilebesiran以及cAPPRicorn-1臨床試驗中的mivelsiran相關的臨床試驗費用增加;
隨着我們開發針對多種組織類型的RNAi治療藥物臨床管線,我們的臨床前活動成本增加。
增加員工薪酬和相關支出,以支持我們的研發管道和開發費用。
部分抵消:
由於在開放標籤延長期間臨床活動的收尾,致使其他臨床項目,尤其是patisiran的APOLLO-b第3期臨床試驗的支出減少。
截至2024年和2023年9月30日止三個月和九個月,與推進合作協議下的活動相關,我們發生了研究和開發費用,主要與外部開發和臨床服務有關,包括臨床產品的製造。
以下表格總結了我們與合作伙伴之間的合作協議直接相關的研發費用,這些費用已經確認爲淨營業收入。
截至9月30日的三個月截至9月30日的九個月
(以千計)2024202320242023
羅氏
$27,756 $— $72,073 $— 
再生元製藥27,856 18,939 60,843 58,254 
其他3,488 3,365 8,117 4,711 
總計$59,100 $22,304 $141,033 $62,965 
銷售、一般及行政費用
銷售、一般及管理費用包括以下內容:
截至9月30日的三個月截至9月30日的九個月
(以千計,百分比除外)20242023$ Change% 變化20242023$ Change% 變化
薪酬及相關信息$89,673 $75,199 $14,474 19 %$277,420 $225,032 $52,388 23 %
諮詢和專業服務68,329 54,187 14,142 26 %191,819 162,723 29,096 18 %
佔用費和所有其他費用36,981 35,007 1,974 %117,633 108,270 9,363 %
基於股票的薪酬26,010 34,782 (8,772)(25)%93,315 101,498 (8,183)(8)%
總計$220,993 $199,175 $21,818 11 %$680,187 $597,523 $82,664 14 %
截至2024年9月30日的三個月和九個月,相對於2023年同期,銷售、一般和管理費用的增加主要是由於與推廣我們的TTR療法相關的市場投資增加以及員工薪酬支出的增加。
我們預計,與2023年相比,我們的研發支出和銷售、總務及管理支出將在2024年繼續增加,因爲我們繼續擴展全球商業和合規性
37

目錄
製造行業,將我們現有的商業產品推向新市場,爲未來商業產品推出做準備,包括推出用於心肌病的AMVUTTRA,假設獲得監管批准,推進我們的候選產品,包括合作項目,進入後續開發階段,推進和發展我們的平台和臨床前管線,並準備監管提交。然而,我們預計某些費用將因製造批次的時間、臨床試驗招募和結果、產品候選人和項目的監管審查,以及基於股票的補償費用而變動,這取決於我們對績效獎勵獲得的概率的決定。
其他(支出)收入
其他(費用)收入包括以下內容:
 截至9月30日的三個月截至9月30日的九個月
(以千美元爲單位,除百分比外)20242023$ 變化百分比變動20242023$ 變化百分比變動
利息支出$(34,376)$(30,893)$(3,483)11 %$(102,887)$(89,883)$(13,004)14 %
利息收入32,146 25,425 6,721 26 %90,973 65,155 25,818 40 %
其他費用,淨額
可交易權益證券的已實現和未實現收益(損失)(1,567)(16,844)15,277 (91)%(2,856)(17,711)14,855 (84)%
發展衍生負債公允價值變動(36,271)(31,209)(5,062)16 %(100,499)(67,895)(32,604)48 %
其他8,310 (9,605)17,915 (187)%3,578 (19,725)23,303 (118)%
總費用$(31,758)$(63,126)$31,368 (50)%$(111,691)$(130,059)$18,368 (14)%
截至2024年9月30日,與2023年同期相比,總其他支出在三個月和九個月內減少,主要是由於市場利率上升推動我們可交易債務券產生了更高的利息收入,以及我們可交易股票持倉的已實現和未實現虧損減少,部分抵消了與開發衍生負債的公允價值變化相關的支出的增加,這是由於由於2024年6月公佈了HELIOS-b臨床試驗的正面頭條結果而導致了估值更新。
所得稅規定
我們記錄了2024年9月30日結束的三個月和九個月的所得稅準備金分別爲290萬美元和1100萬美元,分別爲2023年9月30日結束的三個月和九個月的所得稅準備金300萬美元和650萬美元,主要代表了盈利的外國子公司和州稅的稅費。
我們已評估了涉及我們遞延稅收資產實現性的正面和負面證據。截至2024年9月30日,我們繼續對我們的美國、百慕大和瑞士遞延稅收資產保留全額估值準備。當有足夠的正面證據支持遞延稅收資產能夠實現的結論更可能時,我們將釋放估值準備。在接下來的12個月內,可能會有足夠的積極證據出現,使我們得出結論認爲瑞士部分估值準備不再需要。釋放所有或部分估值準備將導致特定遞延稅收資產的確認,並可能導致釋放記載期間所得稅費用減少的重大減少。
流動性和資本資源
以下表格總結了我們的現金流動情況:
截至9月30日的九個月
(以千爲單位)20242023
淨現金提供(使用):
經營活動$86,350 $133,951 
投資活動$(63,930)$(95,694)
籌資活動$263,162 $132,903 
經營活動
2024年9月30日結束的九個月期間,經營活動提供的淨現金流減少,與2023年同期相比,主要是由於來自合作伙伴的現金收入減少,部分抵消了產品銷售增加帶來的現金收入增加。
38

目錄
投資活動
2024年9月30日結束的九個月內,投資活動使用的淨現金與2023年同期相比有所下降,主要是由於現金淨投資於我們可變債務證券的時機。
籌資活動
2024年9月30日結束的九個月內,融資活動提供的淨現金增加,與2023年同期相比,主要是由於與股票期權行使相關的普通股發行淨款增加。
額外資本要求
目前,我們的項目集中在許多治療領域,並於2024年9月30日獲得監管批准並商業化推出了四種產品。然而,我們正在進行的開發工作可能不會取得成功,我們可能無法推出任何其他產品的銷售或成功擴大我們已批准產品的適應症,包括AMVUTTRA等。此外,由於計劃用於研究和開發活動的運營支出,包括臨床試驗和製造成本,延續拓展晚期臨床、製造、商業和合規能力,包括全球業務,繼續管理和增長我們的知識產權,包括我們的專利組合,合作關係和一般企業活動,我們可能會出現額外的營運虧損。
我們對我們在2023年年度報告10-k表格中描述的預期工作和其他資本需求進行了描述,在「第二部分,項目7. 管理層對財務狀況和經營業績的討論和分析」中。截至2024年9月30日,除了在本季度報告10-Q表格中「總結的綜合財務報表附註」和「流動性和資本資源」部分披露的變化外,我們對我們在2023年年度報告10-k表格中描述的預期工作和其他資本需求沒有發生其他重大變化。
根據我們當前的營運計劃,我們相信截至2024年9月30日的現金、現金等價物和可市場變現證券,再加上我們預計從產品銷售和當前聯盟中獲得的現金,將足以滿足我們接下來至少12個月的資本和運營需求,從本季度10-Q表格的提交日期開始計算。然而,由於在本季度10-Q報告的第II部分第1A條「風險因素」下更詳細描述的諸多因素,我們可能會在比我們當前預期的時間早需求大量額外的所有基金類型,以便繼續商業化我們獲得批准的產品,併爲其開發、進行臨床試驗、製造並且,如果獲批,商業化額外的產品候選者。
事項3.有關市場風險的定量和定性披露
與利率相關的金融市場風險在我們截至2023年12月31日的10-k表格年度報告中進行了描述。截至2024年9月30日,截至2023年12月31日描述的金融市場風險沒有發生重大變化。我們目前不預期在管理公司金融市場風險敞口方面或在管理這些敞口的目標和策略方面會有其他近期變化。
事項4.控制和程序
披露控制程序
我們的管理層與我們的首席執行官(主要執行官)和首席財務官(主要金融官)參與評估了截至2024年9月30日的我們的信息披露控制和程序的有效性。《信息披露控制和程序》一詞的定義,如《交易法》第13a-15(e)和15d-15(e)條所規定,指的是公司設計的用於確保公司在根據《交易法》提交的報告中需要披露的信息被記錄、處理、總結和報告的控制和其他程序,且在SEC規則和表格中規定的時間段內。信息披露控制和程序包括但不限於設計的用於確保公司在根據《交易法》提交的報告中需要披露的信息被累積和傳達給公司管理層,包括其首席執行官和首席財務官,確保在適當時期內做出有關所需披露的及時決策的控制和程序。管理層認識到,無論設計和運營多麼出色,任何控制和程序只能提供合理保證來實現其目標,管理必須運用判斷力來評估可能的控制和程序的成本效益關係。根據我們截至2024年9月30日的信息披露控制和程序的評估,我們的首席執行官和執行副總裁,首席財務官得出結論,截至該日期,我們的信息披露控制和程序在合理保證水平上是有效的。
本季度報告中涵蓋的期間內,在董事長兼首席執行官和首席財務官的參與下,未發現在根據證券交易法規則13a-15(d)或15d-15(d)對我們的財務報告進行內部控制評估的管理評估中的內部控制發生變化,這可能會顯著影響或可能合理地影響我們的財務報告內部控制。
截至2024年9月30日季度結束時,我們的內部財務報告控制沒有發生重大影響或可能重大影響我們的內部財務報告控制。
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第二部分.其他信息
詳見本季度10-Q表中我們的簡明合併財務報表的註釋12——承諾和事項,以獲取有關我們的法律訴訟的信息。
有關未了結的法律訴訟的討論,請閱讀包含在本季度10-Q表格的第I部分,第I款「未經審計的基本財務報表」中的基本財務報表附註13,承諾和或有事項,該部分通過參考併入本項目。
第1A項。風險因素
投資我們的證券存在高度風險。您應該仔細考慮以下風險因素,除了在本季度報告第10-Q表格中所列或參考的其他信息,包括我們的簡明綜合財務報表和相關附註,以及「管理層對財務狀況和經營成果的討論」,以評估我們的公司和我們的業務。如果以下風險中的任何一個,或者我們目前認爲不重要的任何其他風險實際發生,我們的業務、前景、運營結果或財務狀況可能會受到重大和不利影響。在這種情況下,我們的普通股交易價格可能會下跌,您可能會失去全部或部分投資。
我們業務相關重大風險摘要
我們的業務面臨衆多風險和不確定性,更詳細地討論在以下部分中。這些風險包括以下主要風險:
與我們的財務業務結果相關的風險
我們批准的產品或任何未來產品的營銷和銷售可能會不成功,或者不如預期的成功,並且我們可能無法擴大AMVUTTRA的批准適應症。
我們一直在虧損,可能永遠無法變得盈利並保持盈利。
我們將需要大量資金來繼續我們的研究、開發和商業化活動。
任何與Leqvio相關的負面發展都可能對我們未來從諾華騰訊收到的特許權使用費和里程碑付款產生重大不利影響。
與第三方的依賴有關的風險
我們可能無法維持現有的或與可以爲我們的某些產品候選項的開發和商業化提供業務和科學能力以及資金的其他公司建立新的合作關係。
如果任何合作伙伴在與我們的協議中實質性修訂、終止或未履行其義務,可能會導致我們的某些產品候選品的開發和商業化被延遲或終止。
隨着我們不斷增強制造業能力、資源和製造業專長,我們預計將產生重要的成本;與此同時,我們依賴於第三方製造我們的產品,而且預計將繼續依賴於第三方製造我們的產品。
我們依賴第三方進行臨床試驗,如果這些第三方未能履行其義務,我們的開發計劃可能會受到不利影響。
管理我們業務相關的風險
如果我們無法吸引和留住合格的關鍵管理人員和科學家、發展、醫療和商業人員、顧問和顧問,我們實施業務計劃的能力可能會受到不利影響。
隨着我們從一家主要從事發現、臨床前測試和臨床開發的美國和歐洲公司不斷髮展成一個在全球開發和商業化多種藥物、涵蓋亞洲、拉丁美洲和中東等多個地理區域的公司,我們可能會在成功擴大業務方面遇到困難。
與開發、臨床測試、監管批准我們的候選產品以及商業化我們已批准產品相關的行業板塊風險
我們或我們的合作伙伴開發的任何候選產品可能在開發過程中失敗,或延遲到使得該候選產品無法成爲商業上可行的程度。
我們或我們的合作伙伴可能無法獲得美國或國外主管部門對我們或我們合作的候選藥物的批准,因此,我們或我們的合作伙伴可能無法使這些候選藥物商品化。
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即使我們或合作伙伴獲得監管批准,我們的產品仍將受到持續監管監督。
如果執法機關聲稱或判斷我們正在從事與我們未獲批准的產品候選者相關的商業活動,或以違反適用法規的方式推廣我們的商業獲批准產品,我們可能面臨重大責任。
即使我們或我們的合作伙伴獲得監管批准來營銷我們的產品候選者,市場可能不會接受這些產品候選者在其商業推出時,這可能會阻止我們實現盈利。
我們是一家多產品的商業公司,預計將繼續投入大量財務和管理資源,以繼續構建我們的營銷、銷售、市場準入和分銷能力,並進一步建立全球製造行業,但我們的努力可能不會成功。
我們目前市場推廣的任何產品或將來可能開發的產品,都可能受到不利定價監管、第三方報銷實踐或醫療改革舉措的影響,從而損害我們的業務。
與專利、許可證和商業祕密相關的風險
如果我們無法獲得和執行對我們的發現的專利保護,我們開發和商業化產品候選人的能力將受到損害。
我們從第三方所有者那裏獲得專利權許可。如果這些所有者未能正確或成功地取得、維護或執行這些許可下的專利,我們的競爭地位可能會受損。
其他公司或組織可能會挑戰我們的專利權,或主張專利權阻止我們開發和商業化我們的產品。
如果我們捲入知識產權訴訟或其他與權利確定相關的訴訟,包括針對輝瑞公司(Pfizer)以及Moderna公司(Moderna)進行的專利侵權訴訟等,我們可能會承擔巨額成本和費用,而在針對我們的訴訟或程序中,可能會面臨巨額賠償責任,或被要求停止我們的產品開發和商業化努力。
如果我們未能遵守任何許可或相關協議下的義務,可能需要支付損害賠償,並可能喪失發展、商業化和保護我們的干擾核糖核酸,即RNAi技術所必需的許可或其他權利。
與競爭有關的風險
藥品市場競爭激烈。如果我們或我們的合作伙伴無法與現有藥物、新的治療方法和新技術有效競爭,我們或我們的合作伙伴可能無法成功商業化我們或我們的合作伙伴開發的任何藥品。
我們和合作夥伴面臨來自其他公司的競爭,這些公司正在開發類似於我們的新型藥物和技術平台,以及利用新興技術的公司。
與我們的普通股相關的風險
Our stock price has been and may in the future be volatile, and an investment in our common stock could suffer a decline in value.
We expect that results from our and our collaborators’ clinical development activities and the clinical development activities of our competitors will continue to be released periodically and may result in significant volatility in the price of our common stock.
Risks Related to Our Convertible Notes
We may not have sufficient cash flow from our business to pay our indebtedness.
We may not have the ability to raise the funds necessary to settle for cash conversions of our 1% Convertible Senior Notes due 2027, or the Notes, or to repurchase the Notes for cash upon a fundamental change.
The conditional conversion feature of the Notes, if triggered, may adversely affect our liquidity.
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由於我們有很少的運營歷史來評估我們的公司,因此必須考慮早期階段公司經常遇到的問題、支出、困難、複雜性和延遲等問題。
與我們的財務結果相關的風險
我們已經批准的產品或將來的任何產品的營銷銷售可能不成功,或者不如預期成功,我們可能無法拓展某些商業產品,包括AMVUTTRA的批准適應症。
儘管我們已經商業化推出了四款產品,但我們無法預測我們是否能成功營銷和賣出我們批准的產品,或者成功擴大某些商業產品的批准適應症,包括AMVUTTRA。例如,在2022年8月和9月,我們報告了來自於APOLLO-b第3期臨床試驗的帕蒂西蘭的積極安全性和療效結果,該試驗旨在評估帕蒂西蘭對患有併發心肌病的ATTR澱粉樣變性患者的功能能力和生活質量的影響。儘管我們的APOLLO-b臨床試驗獲得了積極的安全性和療效結果,但在2023年10月,FDA發出了一封針對我們關於帕蒂西蘭用於治療併發心肌病ATTR澱粉樣變性的sNDA的完整答覆函,表明帕蒂西蘭對治療併發心肌病ATTR澱粉樣變性的臨床意義尚未得到確立,因此,sNDA不能以其提交的形式獲得批准。
執行我們的業務計劃,到2025年底建立一個盈利的一流生物技術公司,並實現我們的 賽諾菲安萬特P5x25 策略和與此策略相關的指標,除了成功地推廣、銷售和拓展我們批准產品的批准適應症,我們還需要成功:
執行產品開發活動並繼續利用與RNAi和將siRNA傳遞至相關組織和細胞相關的新技術,包括肝臟、中樞神經系統、眼睛、肺部、脂肪和肌肉;
建立並維護強大的知識產權組合;
獲得對我們的產品候選品開發和商業化的監管批准,併成功推廣我們獲批准的產品,以及我們商業化的任何其他產品;
吸引並留住我們產品的客戶;
進入並保持成功的合作;和
隨着臨床試驗、監管批准和商品化導致的成本和費用增加,我們需要管理支出。
如果我們未能實現上述目標,可能無法開發產品候選藥物,成功商業化已獲批准的產品或任何未來產品,籌集資金(如果需要),償還債務,實現財務自給自足或繼續我們的業務。
我們一直在虧損,可能永遠無法變得盈利並保持盈利。
自成立以來,我們一直經歷着顯著的營運虧損。截至2024年9月30日,我們累計赤字達到了72億美元。雖然迄今爲止,我們已在美國、歐盟以及全球各個其他國家推出了四種產品,並預計在2024年及未來在更多國家推出我們獲得商業批准的產品,但我們可能永遠無法實現盈利或運營現金流的正性。截至2024年9月30日止的三個和九個月,我們從ONPATTRO、AMVUTTRA、GIVLAARI和OXLUMO銷售的產品實現淨營業收入分別爲4.201億美元和12億美元。我們可能繼續承擔年度營運虧損,並將在未來幾年需要大量資源,以擴大我們在發現、開發和商業化RNAi治療方面的努力,並計劃在2025年底前實現財務自我可持續性。儘管我們相信我們目前的現金、現金等價物和可出售股票和債券證券,以及我們預計將從產品銷售和我們現有合作中獲得的收入,包括Leqvio銷售里程碑和特許權利金,應能使我們實現自我可持續的環境,而不需要未來的股本融資,但我們將依賴於我們能否產生產品、合作和特許權利金收入來實現該目標。除了從我們當前和未來(如果有)獲得商業批准的產品銷售收入中獲得的收入外,我們預計在未來幾年內,我們產生的部分收入仍將來自於與製藥和生物技術公司(包括Roche、Regeneron、賽諾菲安萬特和諾華)的合作。我們無法確定我們能否繼續保持現有的合作關係,確保並維持新的合作關係,達到我們在合作協議下的義務,或實現可能需要達到或實現以獲得我們現有或新的合作中的支付的里程碑。此外,我們無法確定我們的合作伙伴,包括羅氏和諾華,能否繼續成功履行我們合作協議下的義務,併爲我們創造合作與特許權利金收入。
爲了變得並保持盈利,我們必須成功地發現、開發和商業化具有重要市場潛力的新產品候選藥物。這將需要我們在一系列具有挑戰性的活動中取得成功,包括持續創新平台,進行臨床前測試和臨床試驗階段的開發,獲得新產品候選藥物的監管批准和報銷,以及製造、市場營銷和銷售我們批准的產品。我們可能永遠無法產生足夠重要的收入以實現盈利,即使我們實現了盈利,我們可能無法在季度或年度基礎上維持或增加盈利能力。如果我們無法成爲
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and remain consistently profitable, the market price of our common stock could decline. In addition, we may be unable to raise capital, expand our business, develop additional product candidates or continue our operations.
We will require substantial funds to continue our research, development and commercialization activities, and if we require greater funds than we have estimated, we may need to critically limit, significantly scale back or cease certain activities.
We have used substantial funds to develop our RNAi technologies and will require substantial funds to conduct further research and development activities, including pre-clinical testing and clinical trials of our product candidates, and to manufacture, market and sell our four approved products and any other products that are approved for commercial sale. Because the length of time or scope of activities associated with successful development of our product candidates may be greater than we anticipate, we are unable to estimate the actual funds needed to develop and commercialize our product candidates.
We believe that our current cash, cash equivalents and marketable equity and debt securities, as well as revenue we expect to generate from product sales and under our current collaborations, including milestones and royalties we expect to receive from Novartis on Leqvio sales, will enable us to achieve a self-sustainable financial profile without the need for future equity financing. Nevertheless, our future capital requirements and the period for which our existing resources will support our operations may vary from what we currently expect. We have based our expectations on a number of factors, many of which are difficult to predict or are outside of our control, including:
progress in our research and development programs, including programs in both rare and prevalent diseases, as well as what may be required by regulatory authorities to advance these programs;
the timing, receipt and amount of milestone, royalty and other payments, if any, from present and future collaborators, if any, including milestone and royalty payments from Roche with respect to the development and commercialization of zilebesiran, as well as milestone and royalty payments from Novartis related to the commercialization of Leqvio;
our ability to maintain and establish additional collaborations and/or new business initiatives;
the potential for improved product profiles to emerge from our new technologies and our ability to successfully advance our delivery efforts in extrahepatic tissues;
the resources, time and costs required to successfully initiate and complete our pre-clinical studies and clinical trials, obtain regulatory approvals, prepare for global commercialization of our product candidates and obtain and maintain licenses to third-party intellectual property;
our ability to establish, maintain and operate our own manufacturing facilities in a timely and cost-effective manner;
our ability to manufacture, or contract with third parties for the manufacture of, our product candidates for clinical testing and our products for commercial sale;
the impact of any future pandemics or public health emergencies or the ongoing conflicts in the Middle East and Ukraine on the initiation or completion of pre-clinical studies or clinical trials and the supply of our products or product candidates;
the resources, time and cost required for the preparation, filing, prosecution, maintenance and enforcement of patent claims;
the costs associated with legal activities, including litigation and government investigations, arising in the course of our business activities and our ability to prevail or reach a satisfactory result in any such legal disputes and investigations;
the timing, receipt and amount of sales milestones and royalties, if any, from our approved products and our potential products, if and when approved; and
the outcome of the regulatory review process and commercial success of our products, including AMVUTTRA, and products for which we are entitled to receive royalties, including Leqvio.
If our estimates, predictions and financial guidance relating to these factors are incorrect, we may need to modify our operating plan and may be required to seek additional funding in the future. We may do so through either collaborative arrangements, public or private equity offerings or debt financings, royalty or other monetization transactions or a combination of one or more of these funding sources. Additional funds may not be available to us on acceptable terms or at all.
The terms of any financing we may be required to pursue in the future may adversely affect the holdings or the rights of our stockholders. If we raise additional funds by issuing equity securities, further dilution to our existing stockholders will result. In addition, as a condition to providing additional funding to us, future investors may demand, and may be granted, rights superior to those of existing stockholders.
If we require additional funding and are unable to obtain such funding on a timely basis, we may be required to significantly delay or curtail one or more of our research or development programs, or delay or curtail the further development
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of our global commercial infrastructure, and our ability to achieve our long-term strategic goals may be delayed or diminished. We also could be required to seek funds through arrangements with collaborators or others that may require us to relinquish rights to some of our technologies, product candidates or products that we would otherwise pursue on our own.
Although we sold a portion of the royalty stream and commercial milestones from the global sales of Leqvio by Novartis, we are entitled to retain the remaining portions of the future royalties and commercial milestone payments on Leqvio, and any negative developments related to Leqvio could have a material adverse effect on our receipt of those payments.
In April 2020, we sold to BX Bodyguard Royalties L.P. (an affiliate of The Blackstone Group Inc.), or Blackstone Royalties, 50% of the royalties payable to us with respect to net sales by Novartis, its affiliates or sublicensees of Leqvio and 75% of the commercial milestone payments payable to us under the MDCO License Agreement. If Blackstone does not receive royalty payments in respect of global sales of Leqvio equaling at least $1.00 billion by December 31, 2029, Blackstone Royalties’ interest in Leqvio royalties will increase to 55% (and our interest will decrease to 45%) effective January 1, 2030. As a result, any factor that has an adverse impact on sales of Leqvio could affect our ability to meet the $1.00 billion repayment threshold in this timeframe, which in turn would have a negative impact on the percentage of the Leqvio royalty stream that we are entitled to retain.
Factors that could have an adverse impact on Leqvio sales include:
competitors may develop new therapies or alternative formulations of products for HeFH and ASCVD;
lack of acceptance of Leqvio by patients, the medical community or third party payors;
any negative developments relating to Leqvio, such as safety, efficacy, or reimbursement issues;
any disputes concerning patents or proprietary rights, or under license and collaboration agreements;
foreign currency exchange rate fluctuations; and
adverse regulatory or legislative developments that limit or prohibit the sale of Leqvio, such as restrictions on the use of Leqvio or safety-related label changes, including enhanced risk management programs.
If the revenues generated by sales of Leqvio are lower than expected, we may not receive commercial milestone payments and/or royalties in the amount we are currently anticipating, and our business, prospects, operating results and financial condition could be materially and adversely affected.
If the estimates we make, or the assumptions on which we rely, in preparing our financial statements and/or our projected guidance prove inaccurate, our actual results may vary from those reflected in our projections and accruals.
Our condensed consolidated financial statements have been prepared in accordance with accounting principles generally accepted in the United States of America, or GAAP. The preparation of these condensed consolidated financial statements requires us to make estimates and judgments that affect the reported amounts of our assets, liabilities, revenues and expenses, the amounts of charges accrued by us and related disclosure of contingent assets and liabilities. We base our estimates on historical experience and on various other assumptions that we believe to be reasonable under the circumstances. We cannot assure you, however, that our estimates, or the assumptions underlying them, will be correct.
Further, from time to time we issue financial guidance relating to our expectations regarding our combined product sales, collaboration and royalty revenues, and GAAP and non-GAAP combined research and development and selling, general and administrative expenses, which guidance is based on estimates and the judgment of our management. If, for any reason, our product sales, revenues and/or expenses differ materially from our guidance, we may have to adjust our publicly announced financial guidance. If we fail to meet, or if we are required to change or update any element of, our publicly disclosed financial guidance or other expectations about our business, our stock price could decline.
The investment of our cash, cash equivalents and marketable securities is subject to risks which may cause losses and affect the liquidity of these investments.
As of September 30, 2024, we had $2.78 billion in cash, cash equivalents and marketable securities. We historically have invested these amounts in high–grade corporate notes, commercial paper, securities issued or sponsored by the U.S. government, certificates of deposit and money market funds meeting the criteria of our investment policy, which is focused on the preservation of our capital. Corporate notes may also include foreign bonds denominated in U.S. dollars. These investments are subject to general credit, liquidity, market and interest rate risks. We may realize losses in the fair value of these investments or a complete loss of these investments, which would have a negative effect on our financial condition. In addition, should our investments cease paying or reduce the amount of interest paid to us, our interest income would decline. The market risks associated with our investment portfolio may have an adverse effect on our operating results, liquidity and financial condition.
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Volatility in foreign currency exchange rates could have a material adverse effect on our operating results.
Our revenue from outside of the U.S. is expected to increase as our products, whether commercialized by us or our collaborators, gain marketing approval in such jurisdictions. Our primary foreign currency exposure relates to movements in the Japanese yen, Euro and British pound. If the U.S. dollar weakens against a specific foreign currency, our revenues will increase, having a positive impact on net income, but our overall expenses will increase, having a negative impact. Conversely, if the U.S. dollar strengthens against a specific foreign currency, our revenues will decrease, having a negative impact on net income, but our overall expenses will decrease, having a positive impact. Any future volatility in foreign exchange rates is likely to impact our operating results and financial condition.
Changes in tax laws could adversely affect our business, prospects, operating results and financial condition.
Our business is subject to numerous international, federal, state, and other governmental laws, rules, and regulations that may adversely affect our operating results, including, taxation and tax policy changes, tax rate changes, new tax laws, or revised tax law interpretations, which individually or in combination may cause our effective tax rate to increase. In the U.S., the rules dealing with federal, state, and local income taxation are constantly under review by persons involved in the legislative process and by the Internal Revenue Service and the U.S. Treasury Department. Changes to tax laws (which changes may have retroactive application) could adversely affect us or holders of our common stock. In recent years, many such changes have been made and changes are likely to continue to occur in the future. Future changes in tax laws could have a material adverse effect on our business, prospects, operating results and financial condition.
Additionally, the Organization for Economic Co-operation and Development, or the OECD, the EC, and individual taxing jurisdictions where we and our affiliates do business have recently focused on issues related to the taxation of multinational corporations. The OECD has released its comprehensive plan to create an agreed set of international rules for fighting base erosion and profit shifting. In addition, the OECD, the EC and individual countries are examining changes to how taxing rights should be allocated among countries considering the digital economy. As a result, tax laws in the U.S. and other countries in which we and our affiliates do business could change on a prospective or retroactive basis and any such changes could materially adversely affect our business, prospects, operating results and financial condition.
We may incur additional tax liabilities related to our operations.
We are subject to income tax in the U.S. and the foreign jurisdictions in which we operate. Significant judgment is required in determining our worldwide tax liabilities, and our effective tax rate is derived from the applicable statutory tax rates and relative earnings in each taxing jurisdiction. We record liabilities for uncertain tax positions that involve significant management judgment as to the application of law. Domestic or foreign taxing authorities may disagree with our interpretation of tax law as applied to our and our subsidiaries’ operations or with the positions we may take with respect to particular tax issues on our tax returns. Consequently, tax assessments or judgments in excess of accrued amounts that we have estimated in preparing our financial statements may materially and adversely affect our reported effective tax rate or our cash flows. Further, other factors may adversely affect our effective tax rate, including changes in the mix of our profitability from country to country, tax effects of stock-based compensation (which depend in part on the price of our stock and, therefore, are beyond our control), and changes in tax laws or regulations. For example, the OECD Global Anti-Base Erosion Model have influenced tax laws in countries in which we operate, including the implementation of minimum taxes. Changes to these or other laws and regulations or their interpretations could materially and adversely impact our effective tax rate or cash flows.
Any future outbreaks of pandemics or public health emergencies, may directly or indirectly adversely affect our business, results of operations and financial condition.
In the future, we may experience disruptions from a pandemic or public health emergency that could impact our business and operations, including our ability to successfully commercialize our approved products, and we may not be able to meet expectations with respect to commercial sales as a result. In addition, we may also experience decreased patient demand for our approved products if current or potential patients decide to delay treatment as a result of a pandemic or public health emergency. Business interruptions from pandemics or public health emergencies, including staffing shortages, raw material or other supply chain shortages, production slowdowns and disruptions in delivery systems, may also adversely impact the third parties we or our collaborators rely on in the U.S. and abroad to sufficiently manufacture our approved products and to produce product candidates in quantities we require, which may impair our commercialization efforts, our research and development activities and the potential commercialization of our product candidates.
Additionally, timely completion of pre-clinical activities and initiation of planned clinical trials are dependent upon the availability of, for example, pre-clinical and clinical trial sites, researchers and investigators, patients or healthy volunteer subjects available for recruitment and enrollment, and regulatory agency personnel, which may be adversely affected by global health matters, such as any pandemic or public health emergency. Health regulatory agencies globally may also experience disruptions in their operations as a result of a pandemic or future public health emergency, which could impact review, inspection and approval timelines.
While the ultimate impact of any pandemic or public health emergency on our business is uncertain, any negative impacts of such pandemic or public health emergency, alone or in combination with others, could exacerbate other risk factors discussed
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herein. The full extent to which any pandemic or public health emergency, will negatively affect our operations, financial performance, and stock price will depend on future developments that are highly uncertain and cannot be predicted.
Risks Related to Our Dependence on Third Parties
If we are unable to maintain our existing collaborations, or enter into new collaborations with other companies that can provide business and scientific capabilities and funds for the development and commercialization of our product candidates, it may have a negative impact on our business, prospects, operating results and financial condition.
We do not currently have adequate capacity or capabilities to advance all opportunities arising from our growing pipeline of RNAi therapeutics. Accordingly, we have entered into collaborations with third party collaborators we believe can provide such capacity and capabilities in certain territories and/or for certain product candidates, and we intend to enter into additional such collaborations in the future. Specifically, we currently have active collaborations with, among others, Roche, Regeneron, Sanofi, and Novartis covering various products and product candidates in our pipeline.
In such collaborations, we expect our current, and may expect our future, collaborators to provide substantial capabilities in clinical development, regulatory affairs, and/or marketing, sales and distribution. Under certain of our collaborations, we also expect our collaborators to develop, market and/or sell certain of our product candidates, in certain territories or globally, and we have limited or no control over the development, sales, marketing and distribution activities of these collaborators. Our future revenues may depend heavily on the success of the efforts of these third parties. For example, we will rely entirely on (i) Regeneron for the development and commercialization of all programs targeting eye diseases (subject to limited exceptions), and potentially other CNS and liver programs; (ii) Novartis for the development and commercialization of Leqvio worldwide; (iii) Sanofi for the development and commercialization of fitusiran worldwide; and (iv) Roche for the commercialization of zilebesiran outside of the U.S. In the case of each collaboration referenced in clauses (i)-(iv) above, we are entitled to royalties, and in some instances commercial milestone payments, on the sales of the applicable product. If our collaborators are not successful in their development and/or commercialization efforts, our future revenues from the relevant product or product candidate may be adversely affected. For example, in December 2020 Novartis received a CRL from the FDA stating that the FDA could not approve the NDA by the PDUFA action date due to unresolved inspection-related conditions at a third party manufacturing facility. While Leqvio was ultimately approved by the FDA in December 2021, the resolution of the CRL resulted in a delay in the payment of an approval milestone and potential U.S. royalties. As discussed above, under our agreement with Blackstone Royalties, if the revenues generated by the royalties received by Blackstone Royalties from us with respect to Leqvio sales do not reach a certain level by the end of 2029, Blackstone Royalties will be entitled to a higher royalty percentage beginning in 2030, which would have an adverse impact on our royalty revenues beginning in 2030.
We may not be successful in entering into future collaborations on terms favorable to us due to various factors, including our ability to demonstrate improved product profiles from our new technologies, including our IKARIA platform, our ability to successfully demonstrate proof-of-concept for our technology in humans in certain tissues or disease areas, our ability to demonstrate the safety and efficacy of our specific product candidates, our ability to manufacture or have third parties manufacture RNAi therapeutics, the strength of our intellectual property portfolio and/or concerns around challenges or potential challenges to our intellectual property portfolio. Even when we succeed in securing such new collaborations, we may not be able to maintain them if, for example, development or approval of a product candidate is delayed, challenges are raised as to the validity or scope of our intellectual property, we are unable to secure adequate reimbursement from payors, sales of an approved drug are lower than we expected, or our collaborator changes its strategic focus.
Furthermore, any delay in entering into new collaboration agreements would have the potential to prevent or delay the development and commercialization of certain product candidates, or reduce the competitiveness such product candidates if they ultimately reach the market, which in turn could adversely affect our business, prospects, operating results and financial condition.
For certain product candidates, we have formed collaborations to fund all or part of the costs of drug development and commercialization, such as our collaborations with Roche, Regeneron, Sanofi and Novartis. We may not, however, be able to enter into additional collaborations for certain other programs, and the terms of any collaboration agreements we do secure may not be favorable to us. If we are not successful in our efforts to enter into future collaboration arrangements with respect to one or more of our product candidates, we may not have sufficient funds or other resources to develop these product candidates or other product candidates internally, or to bring such product candidates to market. In these circumstances, we will not be able to generate revenues from these product candidates, and this will substantially harm our business, prospects, operating results and financial condition.
If any collaborator materially amends, terminates or fails to perform its obligations under agreements with us, the development and commercialization of our product candidates could be delayed or terminated.
Our dependence on collaborators for capabilities and funding means that our business could be adversely affected if any collaborator materially amends or terminates its collaboration agreement with us or fails to perform its obligations under that agreement. Our current or future collaborations, if any, may not be scientifically or commercially successful. Disputes may arise in the future with respect to the ownership of rights to technology or products developed with collaborators, which could
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have an adverse effect on our ability to develop and commercialize any affected product candidate. Our current collaborations allow, and we expect that any future collaborations will allow, either party to terminate the collaboration for a material breach by the other party. In addition, our collaborators may have additional termination rights for convenience with respect to the collaboration or a particular program under the collaboration, under certain circumstances. For example, our agreement with Novartis relating to the development and commercialization of inclisiran worldwide may be terminated by Novartis at any time upon four months’ prior written notice, provided if the agreement is terminated by Novartis for convenience, Novartis must grant a license to us under certain technology developed in the course of its (or MDCO’s) activities under the agreement, subject to a royalty to be negotiated between the parties. Moreover, any adverse actions by Novartis with respect to the MDCO License Agreement or disputes with Novartis regarding the MDCO License Agreement could adversely impact our ability to comply with our obligations under our agreements with Blackstone Royalties. If we were to lose a commercialization collaborator, we would have to attract a new collaborator (potentially on less favorable terms for us than we have with our existing collaborator) or develop expanded sales, distribution and marketing capabilities internally, which would require us to invest significant amounts of financial and management resources.
In addition, if we have a dispute with a collaborator over the ownership of technology or other matters, or if a collaborator terminates its collaboration with us, for breach or otherwise, or determines not to pursue the research, development and/or commercialization of the affected product or product candidate, it could delay our development of product candidates, result in the need for additional company resources to develop product candidates, require us to expend time and resources to develop expanded sales and marketing capabilities on a more expedited timeline, make it more difficult for us to attract new collaborators and could adversely affect how we are perceived in the business and financial communities.
Moreover, a collaborator, or in the event of a change in control of a collaborator or the assignment of a collaboration agreement to a third party, the successor entity or assignee, as in the case of MDCO and Novartis, could determine that it is in its interests to:
pursue alternative technologies or develop alternative products, either on its own or jointly with others, that may be competitive with the products on which it is collaborating with us or which could affect its commitment to the collaboration with us;
pursue higher-priority programs or change the focus of its development programs, which could affect the collaborator’s commitment to us; or
if it has marketing rights, choose to devote fewer resources to the marketing of our product candidates, if any are approved for marketing, than it does for product candidates developed without us.
If any of these occur, the development and commercialization of one or more products or product candidates could be delayed, curtailed or terminated because we may not have sufficient financial resources or capabilities to continue such development and commercialization on our own.
We expect to incur significant costs as we continue to grow our manufacturing capabilities and resources and develop manufacturing expertise; in the meantime, we rely, and expect to continue to rely, on third parties to manufacture our products. The loss of these or future third-party suppliers, or their inability to provide us with sufficient supply, could harm our business.
We have been expanding our manufacturing capabilities, and in order to continue to commercialize our approved products, continue to develop our current product candidates, apply for regulatory approvals and, if approved, commercialize future products, we will need to continue to develop our internal manufacturing capabilities and/or contract or otherwise arrange for any necessary external manufacturing capabilities. Historically, our internal manufacturing capabilities were limited to small-scale production of material for use in in vitro and in vivo experiments and such material was not required to be produced under current good manufacturing practice standards, or cGMP. During 2012, we developed cGMP capabilities and processes for the manufacture of patisiran formulated bulk drug product for late-stage clinical trial use and commercial supply. In addition, during 2020, we completed construction and qualification of our cGMP manufacturing facility in Norton, Massachusetts where we manufacture drug substances for early-stage clinical development and have the possibility to manufacture drug substances for late-stage clinical development and commercial use, in the future.
At the present time, we only have the capacity to manufacture limited quantities of clinical trial drug substance ourselves, and otherwise we continue to rely on third party CMOs to manufacture additional drug substance, and we rely on third party CMOs for all of our drug product requirements for clinical and commercial use. There are a limited number of CMOs worldwide with the expertise to manufacture our siRNA therapeutic products, and we currently rely on a limited number of CMOs in North America, Europe and Asia to manufacture our products and product candidates. There are risks inherent in pharmaceutical manufacturing that could affect the ability of our CMOs to meet our delivery time requirements or provide adequate amounts of material to meet our needs, and if our CMOs fail to do these things it could delay our clinical trials and potentially put our commercial supply at risk, as well as result in additional expense to us. To fulfill our future requirements, we will likely need to contract with additional CMOs, and such alternative suppliers may be limited, not be readily available, or we may be unable to enter into agreements with them on reasonable terms and in a timely manner, or at all.
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In addition to the manufacture of synthetic siRNAs, we may have additional manufacturing requirements related to the technology required to deliver the siRNA to the relevant cell or tissue type, such as LNPs or conjugates or other drug delivery technologies. In some cases, the delivery technology we utilize is highly specialized or proprietary, and for technical and/or legal reasons, we may have access to only one or a limited number of potential manufacturers for such delivery technology. In addition, the scale-up of our delivery technologies could be very difficult and/or take significant time. We also have limited experience in such scale-up and manufacturing, requiring us to depend on a limited number of third parties, who might not be able to deliver in a timely manner, or at all. Failure by manufacturers to properly manufacture our delivery technology and/or formulate our siRNAs for delivery could result in unusable product, supply delays and drug shortages. Furthermore, competition for supply from our manufacturers from other companies, a breach by such manufacturers of their contractual obligations or a dispute with such manufacturers would cause delays in our discovery and development efforts, as well as additional expense to us.
In developing manufacturing capabilities by building our own manufacturing facilities, we have incurred substantial expenditures, and expect to incur significant additional expenditures in the future. Also, we have had to, and will likely need to continue to, recruit, hire, and train qualified employees to staff our facilities. If we are unable to manufacture sufficient quantities of material or if we encounter problems with our facilities in the future, we may also need to secure alternative suppliers, and such alternative suppliers may not be available, or we may be unable to enter into agreements with them on reasonable terms and in a timely manner, or at all. Given our dependence on a limited number of CMOs to supply our commercial products and clinical candidates, and the ongoing utilization of our own facilities, any delay or setback in the manufacture of our products could impede ongoing clinical and commercial supply, which could materially and adversely impact our business, prospects, operating results or financial condition. In addition, to the extent we or our collaborators rely on CMOs to supply our product candidates, any delays or disruptions in supply could have a material adverse impact on the research and development activities and potential commercialization of our or our collaborators’ product candidates.
The manufacturing processes for our products and any other product candidates that we may develop is subject to the FDA and foreign regulatory authority approval processes and we will need to meet, and will need to contract with CMOs who can meet, all applicable FDA and foreign regulatory authority requirements on an ongoing basis. The failure of any CMO to meet required regulatory authority requirements could result in the delayed submission of regulatory applications, or delays in receiving regulatory approval for any of our or our current or future collaborators’ product candidates. For example, in April 2022, due to an amendment to our vutrisiran NDA submission to address a pending inspection classification at a third-party secondary packaging and labeling facility, the FDA extended the review timeline of the NDA. In addition, if we receive the necessary regulatory approval for any product candidate, we also expect to rely on third parties, including potentially our commercial collaborators, to produce materials required for commercial supply.
Additionally, in January 2024, the U.S. House of Representatives introduced the BIOSECURE ACT (H.R. 7085), which was subsequently amended on May 15, 2024 and passed by the U.S. House of Representatives on September 9, 2024, and the Senate advanced a substantially similar bill (S.3558), both of which would prohibit U.S. federal executive agencies from contracting with any entity where the biotechnology equipment or services of a “biotechnology company of concern” would be used in the performance of that contract. Generally, a “biotechnology company of concern” is a biotechnology company that is subject to the jurisdiction, direction, control, or operates on behalf of a foreign adversary’s government and poses a risk to the national security of the U.S. The final language, pathway and timing for either of these bills or their provisions to become law remain uncertain. Nonetheless, if these bills became law, or similar laws are passed, they would have the potential to severely restrict our ability to purchase services or products from, or otherwise collaborate with, certain Chinese “biotechnology companies of concern” without losing the ability to contract with, or otherwise receive reimbursement from, the U.S. government. We do business with companies in China and it is possible some of our contractual counterparties could be impacted by the legislation described above and alternative arrangements may need to be made.
If the third parties we engage to supply materials or manufacture product candidates or products for preclinical testing or clinical or commercial supply should cease to do so for any reason, we would likely experience delays in advancing these preclinical tests and clinical trials and/or interruptions in commercial supply while we identify and qualify replacement suppliers or manufacturers, and we may be unable to obtain replacement supplies on terms that are favorable to us, or at all. If we are not able to obtain adequate supplies of our product candidates or products or the substances used to manufacture them, it could materially and adversely impact our business, prospects, operating results or financial condition.
To the extent that we have existing, or enter into future, manufacturing arrangements with third parties, we depend, and will depend in the future, on these third parties to perform their obligations in a timely manner and consistent with contractual and regulatory requirements, including those related to quality control and quality assurance. The failure of any CMO to perform its obligations as expected, or, to the extent we manufacture all or a portion of our product candidates ourselves, our failure to execute on our manufacturing requirements, could adversely affect our business in a number of ways, including:
we or our current or future collaborators may not be able to initiate or continue clinical trials of product candidates that are under development;
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we or our current or future collaborators may be delayed in submitting regulatory applications, or receiving regulatory approvals, for our product candidates;
we may lose the cooperation of our collaborators;
our facilities and those of our CMOs, and our products could be the subject of inspections by regulatory authorities that could have a negative outcome and result in supply delays;
we may be required to cease distribution or recall some or all batches, of our products or take action to recover clinical trial material from clinical trial sites; and
ultimately, we may not be able to meet the clinical and commercial demands for our product candidates and products.
We rely on third parties to conduct our clinical trials, and if such third parties fail to fulfill their obligations, our development plans may be adversely affected.
We rely on independent clinical investigators, CROs, and other third-party service providers to assist us in managing, monitoring and otherwise carrying out our clinical trials. We have contracted with, and we plan to continue to contract with, certain third parties to provide certain services, including site selection, enrollment, monitoring, auditing and data management services. These investigators and CROs are not our employees and we have limited control over the amount of time and resources they dedicate to our programs. These third parties may have contractual relationships with other entities, some of which may be our competitors, which may draw their time and resources away from our programs. Although we depend heavily on these parties, we control only limited aspects of their activity and therefore, we cannot be assured that these third parties will adequately perform all of their contractual obligations to us in compliance with regulatory and other legal requirements and our internal policies and procedures. Nevertheless, we are responsible for ensuring that each of our studies is conducted in accordance with the applicable protocol, legal, regulatory and scientific standards, and our reliance on third parties does not relieve us of our regulatory responsibilities. We and our CROs are required to comply with applicable good clinical practice, or GCP, requirements, which are regulations and guidelines enforced by the FDA and comparable foreign regulatory authorities for our product candidates in clinical development, and to implement timely corrective action to address any non-compliance. Regulatory authorities enforce these GCP requirements through periodic inspections of trial sponsors, principal investigators and trial sites, including in connection with the review of marketing applications. If we or any of our CROs fail to comply with applicable GCP requirements, or fail to take any such corrective action, the clinical data generated in our clinical trials may be deemed unreliable and the FDA, EMA, PMDA or other foreign regulatory authorities may require us to take additional action or perform additional clinical trials before approving our marketing applications. We cannot assure you that upon inspection by a given regulatory authority in the future, such regulatory authority will determine that any of our clinical trials comply with GCP regulations.
If our third-party service providers cannot adequately and timely fulfill their obligations to us for any reason, or if the quality and accuracy of our clinical trial data is compromised due to failure by such third party service provider to adhere to our protocols or regulatory requirements or if such third party service providers otherwise fail to meet deadlines, our development plans and/or regulatory reviews for marketing approvals may be delayed or terminated. As a result, our business, prospects, operating results and financial condition would be harmed, and our stock price would likely be negatively impacted.
Before conducting clinical trials to demonstrate the safety and efficacy of our product candidates in humans in support of IND applications or similar applications in other jurisdictions, we must complete pre-clinical studies, which includes animal studies. In addition, we rely on third-party service providers to source certain materials for such pre-clinical studies. Our ability to complete our pre-clinical studies is contingent on, among other things, our ability to source animals and other supplies required for the conduct of such studies. If we are unable to obtain such supplies, we may be unable to complete such pre-clinical studies in a timely manner or at all.
Risks Related to Managing Our Operations
If we are unable to attract and retain qualified key management and scientists, development, medical and commercial staff, consultants and advisors, our ability to implement our business plan may be adversely affected.
We are highly dependent upon our senior management and our scientific, clinical, sales and medical staff. The loss of the service of any members of our senior management could significantly delay or prevent the achievement of product development and commercialization, and other business objectives, and adversely impact our stock price. Our employment arrangements with our key personnel are terminable without notice. We do not carry key person life insurance on any of our employees.
We have grown our workforce significantly over the past several years and anticipate additional employee growth in the future, and we face intense competition for qualified individuals from numerous pharmaceutical and biotechnology companies, universities, governmental entities and other research institutions, many of which have substantially greater resources to attract and reward qualified individuals than we do. In addition, if we are not successful in commercializing our approved products, we may be unable to attract and retain highly qualified sales and marketing professionals, and if we are not able to attract and retain qualified sales and marketing professionals, it would negatively impact our ability to commercialize our approved products and any future products. Accordingly, we may be unable to attract and retain suitably qualified individuals to support our growing
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research, development and global commercialization efforts and initiatives, and our failure to do so could have an adverse effect on our ability to implement our future business plans.
We may have difficulty expanding our operations successfully as we continue our evolution from a U.S.- and EU-based company primarily involved in discovery, pre-clinical testing and clinical development into a global company that develops and commercializes multiple products.
As we continue the commercial launches of our approved products and increase the number of product candidates we are developing, we will need to continue to expand our operations in the U.S. and further develop operations in the EU and other geographies, including Asia and Latin America. To date, we have received regulatory approval for four products, which we have launched in multiple geographies globally, and we continue to expand the reach of these products with additional regulatory filings and launches.
We have grown our workforce significantly over the last several years and anticipate additional employee growth globally in the future as we focus on the commercialization of our approved products, and achieving our Alnylam P5x25 strategy. This growth has placed a strain on our administrative and operational infrastructure and, as a result, we will need to continue to develop additional and/or new infrastructure and capabilities to support our growth and obtain additional space to conduct our global operations in the U.S., EU, Japan, Latin America and other geographies. If we are unable to develop such additional infrastructure or obtain sufficient space to accommodate our growth in a timely manner and on commercially reasonable terms, our business could be negatively impacted. As we continue the commercialization of our approved products, and as the product candidates we develop enter and advance through clinical trials, we will need to continue to expand our global development, regulatory, manufacturing, quality, compliance, and marketing and sales capabilities, or contract with other organizations to provide these capabilities for us. In addition, as our operations continue to expand, we will need to successfully manage additional relationships with various collaborators, suppliers, distributors and other organizations. Our ability to manage our operations and future growth will require us to continue to enhance our operational, financial and management controls and systems, reporting systems and infrastructure, ethics and compliance functions, and policies and procedures. We may not be able to implement enhancements to our management information and control systems in an efficient or timely manner and may discover deficiencies in existing systems and controls.
The use of social media presents risks and challenges.
We use social media to communicate about our clinical development programs and the diseases our investigational RNAi therapeutics are being developed to treat, including in connection with our commercialization efforts for our approved products. We intend to do the same for our future products, if approved. While we believe our social media use is appropriate under current regulatory guidance, social media practices in the biopharmaceutical industry continue to evolve and regulations and regulatory guidance relating to such use are evolving and not always clear. This evolution creates uncertainty and risk of noncompliance with regulations applicable to our business, resulting in potential regulatory actions against us, along with the potential for litigation related to off-label marketing or other prohibited activities. For example, for our clinical-stage candidates, patients may use social media channels to comment on their experience in an ongoing blinded clinical trial or to report an alleged adverse event, or AE. When such disclosures occur, there is a risk that trial enrollment may be adversely impacted, that we may fail to monitor and comply with applicable AE reporting obligations or that we may not be able to defend our business in the face of the political and market pressures generated by social media due to restrictions on what we may say about our investigational products. There is also a risk of inappropriate disclosure of sensitive information or negative or inaccurate posts or comments about us on any online platform, including a blog on the internet, or a post on a website, that can be distributed rapidly and could negatively harm our reputation. If any of these events were to occur or we otherwise fail to comply with applicable regulations, we could incur liability, face regulatory actions or incur other harm to our business.
Our business and operations could suffer in the event of system failures or unauthorized or inappropriate use of or access to our systems.
We are increasingly dependent on our information technology systems and infrastructure for our business. We collect, store and transmit sensitive information including intellectual property, proprietary business information, including highly sensitive clinical trial data, and personal information in connection with our business operations. The secure maintenance of this information is critical to our operations and business strategy. Some of this information could be subject to criminal attack or unauthorized access and use by third parties with a wide range of motives and expertise, including organized criminal groups, “hacktivists,” patient groups, disgruntled current or former employees and others. Cyber-attacks are of ever-increasing levels of sophistication, and despite our security measures, our information technology and infrastructure may be vulnerable to such attacks or may be breached, including due to employee error or malfeasance.
The pervasiveness of cybersecurity incidents in general and the risks of cyber-crime are complex and continue to evolve. Although we are making significant efforts to maintain the security and integrity of our information systems and are exploring various measures to manage the risk of a security breach or disruption, there can be no assurance that our security efforts and measures will be effective or that attempted security breaches or disruptions would not be successful or damaging. Despite the implementation of security measures, our internal computer systems and those of our contractors, consultants and collaborators are vulnerable to damage or interruption from computer viruses, unauthorized or inappropriate access or use, natural disasters,
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pandemics or public health emergencies, terrorism, war (including the ongoing conflicts in Ukraine and the Middle East), and telecommunication and electrical failures. Such events could cause interruption of our operations. For example, the loss of pre-clinical trial data or data from completed or ongoing clinical trials for our product candidates could result in delays in our regulatory filings and development efforts, as well as delays in the commercialization of our products, and significantly increase our costs. To the extent that any disruption, security breach or unauthorized or inappropriate use or access to our systems were to result in a loss of or damage to our data, or inappropriate disclosure of confidential or proprietary information, including but not limited to patient, employee or vendor information, we could incur notification obligations to affected individuals and government agencies, liability, including potential lawsuits from patients, collaborators, employees, stockholders or other third parties, and liability under foreign, federal and state laws that protect the privacy and security of personal information, and the development and potential commercialization of our product candidates could be delayed.
In addition, our increased use of cloud technologies heightens these third party and other operational risks, and any failure by cloud or other technology service providers to adequately safeguard their systems and prevent cyber-attacks could disrupt our operations and result in misappropriation, corruption, or loss of confidential or propriety information. The risk of cyber-attacks is increased with employees working remotely. Remote work increases the risk we may be vulnerable to cybersecurity-related events such as phishing attacks and other security threats.
Risks Related to Our Industry
Risks Related to Development, Clinical Testing and Regulatory Approval of Our Product Candidates and the Commercialization of Our Approved Products
Any product candidate we or our collaborators develop may fail in development or be delayed to a point where such product candidate does not become commercially viable.
Before obtaining regulatory approval for the commercial distribution of our product candidates, we must conduct, at our own expense, extensive nonclinical tests and clinical trials to demonstrate the safety and/or efficacy in humans of our product candidates. Nonclinical and clinical testing is expensive, difficult to design and implement, can take many years to complete and is uncertain as to outcome, and the historical failure rate for product candidates is high. We currently have multiple programs in clinical development, including internal and collaborated programs in Phase 3 development, as well as several earlier-stage clinical programs. However, we may not be able to further advance any of our product candidates through clinical trials and regulatory approval.
If we enter into clinical trials, the results from nonclinical testing or early or late-stage clinical trials of a product candidate may not predict the results that will be obtained in subsequent subjects or in subsequent human clinical trials of that product candidate or any other product candidate. For example, we recently reported positive results from the HELIOS-B Phase 3 clinical trial of vutrisiran for the treatment of patients with ATTR amyloidosis with cardiomyopathy. While vutrisiran demonstrated positive results in the clinical trial, we cannot be certain that the results from HELIOS-B will support approval of vutrisiran for the treatment of patients with ATTR amyloidosis with cardiomyopathy. There is a high failure rate for drugs proceeding through clinical trials. A number of companies in the pharmaceutical and biotechnology industries have suffered significant setbacks in clinical development even after achieving promising results in earlier studies, and any such setbacks in our clinical development, including with respect to vutrisiran, could have a material adverse effect on our business, prospects, operating results and financial condition. Moreover, certain of our product candidates employ novel delivery technologies that have yet to be extensively evaluated in human clinical trials and proven safe and effective.
Additionally, several of our planned and ongoing clinical trials utilize an “open-label” trial design. An “open-label” clinical trial is one where both the patient and investigator know whether the patient is receiving the investigational product candidate or either an existing approved drug or placebo. Most typically, open-label clinical trials test only the investigational product candidate and sometimes may do so at different dose levels. Open-label clinical trials are subject to various limitations that may exaggerate any therapeutic effect as patients in open-label clinical trials are aware when they are receiving treatment. Accordingly, open-label clinical trials may be subject to a “patient bias” where patients perceive their symptoms to have improved merely due to their awareness of receiving an experimental treatment. In addition, open-label clinical trials may be subject to an “investigator bias” where those assessing and reviewing the physiological outcomes of the clinical trials are aware of which patients have received treatment and may interpret the information of the treated group more favorably given this knowledge. The results from an open-label trial may not be predictive of future clinical trial results with any of our product candidates when studied in a blinded, controlled environment with a placebo or active control.
In addition, we, the FDA or other applicable regulatory authorities, or an institutional review board, or IRB, or similar foreign review board or committee, may delay initiation of or suspend clinical trials of a product candidate at any time for various reasons, including if we or they believe the healthy volunteer subjects or patients participating in such trials are being exposed to unacceptable health risks. Among other reasons, adverse side effects of a product candidate or related product on healthy volunteer subjects or patients in a clinical trial could result in our decision, or a decision by the FDA or foreign regulatory authority, to suspend or terminate the clinical trial, or, in the case of regulatory agencies, a refusal to approve a particular product candidate for any or all indications of use.
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Clinical trials of a new product candidate require the enrollment of a sufficient number of patients, including patients who are suffering from the disease the product candidate is intended to treat and who meet other eligibility criteria. Rates of patient enrollment are affected by many factors, including the size of the patient population, the age and condition of the patients, the stage and severity of disease, the availability of clinical trials for other investigational drugs for the same disease or condition, the nature of the protocol, the proximity of patients to clinical sites, the availability of effective treatments for the relevant disease, and the eligibility criteria for the clinical trial. We or our collaborators may experience difficulty enrolling our clinical trials due to the availability of existing approved treatments, as well as other investigational treatments in development. For example, in November 2018 we announced that due to recruitment challenges, we had discontinued a Phase 2 clinical trial of cemdisiran in atypical hemolytic uremic syndrome and were focusing our cemdisiran clinical development efforts in a different indication. Delays or difficulties in patient enrollment, or difficulties retaining trial participants, including as a result of the availability of existing approved treatments or other investigational treatments or safety concerns, including the impact of pandemics or other public health emergencies, can result in increased costs, longer development times or termination of a clinical trial.
Although our RNAi therapeutics have been generally well-tolerated in our clinical trials to date, new safety findings may emerge. The occurrence of serious adverse events, or SAEs, and/or adverse events, or AEs, can result in the suspension or termination of clinical trials of a product candidate by us, our collaborators, or the FDA or a foreign regulatory authority, and may negatively impact the clinical and/or regulatory timelines of the impacted product candidates. For example, in October 2016, we discontinued our revusiran program and in September 2017, we announced that we had temporarily suspended dosing in all ongoing fitusiran studies pending further review of a fatal thrombotic SAE that occurred in a patient who was receiving fitusiran in our Phase 2 OLE clinical trial.
In addition, the occurrence of SAEs and/or AEs could also result in refusal by the FDA or a foreign regulatory authority to approve a particular product candidate for any or all indications of use, or in limitations in the label of any approved product.
Clinical trials also require the review, oversight and approval of IRBs, or, outside of the U.S., independent ethics committees, which continually review clinical investigations and protect the rights and welfare of human subjects. Inability to obtain or delay in obtaining IRB or ethics committee approval can prevent or delay the initiation and completion of clinical trials, and the FDA or foreign regulatory authorities may decide not to consider any data or information derived from a clinical trial not subject to initial and continuing IRB or ethics committee review and approval, as the case may be, in support of a marketing application.
Our product candidates that may encounter problems during clinical trials that will cause us, an IRB, ethics committee or regulatory authorities to delay, suspend or terminate these clinical trials, or that will delay or confound the analysis of data from these clinical trials. If our product candidates experience any such problems, we may not have the financial resources necessary to continue development of the affected product candidate or any of our other product candidates. We may also lose, or be unable to enter into, collaborative arrangements for the affected product candidate or any of our other product candidates.
A failure of one or more of our clinical trials can occur at any stage of testing. We may experience numerous unforeseen events during, or as a result of, nonclinical testing and the clinical trial process that could extend our clinical development timelines and delay or prevent regulatory approval or our ability to commercialize our product candidates, including:
our nonclinical tests or clinical trials may produce negative or inconclusive results, and we may decide, or regulators may require us, to conduct additional nonclinical testing or clinical trials, or we may abandon projects that have the potential to be promising;
delays in filing IND applications or comparable foreign applications or delays or failure in obtaining the necessary approvals from regulators or IRBs/ethics committees in order to commence a clinical trial at a prospective trial site, or their suspension or termination of a clinical trial once commenced;
conditions imposed on us by an IRB or ethics committee, or the FDA or comparable foreign regulatory authorities regarding the scope or design of our clinical trials;
problems in engaging IRBs or ethics committees to oversee clinical trials or problems in obtaining or maintaining IRB or ethics committee approval of clinical trials;
delays in enrolling patients and volunteers into clinical trials, and variability in the number and types of patients and volunteers available for clinical trials, including as a result of the COVID-19 pandemic, a future pandemic or public health emergency and the ongoing conflict in Ukraine;
disruptions caused by man-made or natural disasters or pandemics, epidemics or public health emergencies or other business interruptions;
high drop-out rates for patients and volunteers in clinical trials;
negative or inconclusive results from our clinical trials or the clinical trials of others for product candidates similar to ours;
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inadequate supply or quality of product candidate materials or other materials necessary for the conduct of our clinical trials or disruption or delays in clinical supply due to a future pandemic or public health emergency;
greater than anticipated clinical trial costs;
serious and unexpected drug-related side effects experienced by patients taking our approved products, participants in our clinical trials or individuals using drugs similar to our products or product candidates;
poor or disappointing effectiveness of our product candidates during clinical trials;
unfavorable FDA or other regulatory agency inspection and review of a clinical trial site or records of any clinical or nonclinical investigation;
failure of our third-party contractors or investigators to comply with regulatory requirements, including GCP and cGMP, or otherwise meet their contractual obligations in a timely manner, or at all;
governmental or regulatory delays and changes in regulatory requirements, policy and guidelines, including the imposition of additional regulatory oversight around clinical testing generally or with respect to our technology in particular; or
interpretations of data by the FDA and similar foreign regulatory agencies that differ from ours.
Even if we successfully complete clinical trials of our product candidates, any given product candidate may not prove to be a safe and effective treatment for the disease for which it was being tested.
We or our collaborators may be unable to obtain U.S. or foreign regulatory approval for our or our collaborated product candidates and, as a result, we or our collaborators may be unable to commercialize such product candidates.
Our and our collaborated product candidates are subject to extensive governmental regulations relating to, among other things, research, testing, development, manufacturing, safety, efficacy, approval, recordkeeping, reporting, labeling, storage, pricing, marketing and distribution of drugs. Rigorous nonclinical testing and clinical trials and an extensive regulatory approval process are required to be successfully completed in the U.S. and in many foreign jurisdictions before a new drug can be marketed. Satisfaction of these and other regulatory requirements is costly, time consuming, uncertain and subject to unanticipated delays. It is possible that the product candidates we and our collaborators are developing will not obtain the regulatory approvals necessary for us or our collaborators to begin selling them, or, in the case of vutrisiran, will not obtain regulatory approval to be sold for an additional, broader indication than the indication for which it is currently approved. It is also possible that the FDA or other regulatory authorities may determine that the data generated in clinical trials for a product candidate is not sufficient to support the approval of an application for regulatory approval. For example, although we reported positive results from the APOLLO-B Phase 3 clinical trial of patisiran in patients with ATTR amyloidosis with cardiomyopathy, in October 2023, the FDA issued a CRL in response to our sNDA for patisiran, indicating the sNDA could not be approved in its present form.
The time required to obtain FDA and other regulatory approvals is unpredictable but typically takes many years following the commencement of clinical trials, depending upon the type, complexity and novelty of the product candidate. The standards that the FDA and its foreign counterparts use when regulating us are not always applied in a predictable or uniform manner and can change over time. Any analysis we perform of data from nonclinical and clinical activities is subject to confirmation and interpretation by regulatory authorities, which could delay, limit or prevent regulatory approval. We or our collaborators may also encounter unexpected delays or increased costs due to new government regulations, for example, from future legislation or administrative action, or from changes in FDA policy during the period of product development, clinical trials and FDA regulatory review. It is impossible to predict whether legislative changes will be enacted, or whether FDA or foreign regulations, guidance or interpretations will be changed, or what the impact of such changes, if any, may be.
Because the product candidates we or our collaborators are developing represent a new class of drug, the FDA and its foreign counterparts have not yet established any definitive policies, practices or guidelines in relation to these drugs. The lack of policies, practices or guidelines may hinder or slow review by the FDA of any regulatory filings that we or our collaborators may submit. Moreover, the FDA may respond to these submissions by defining requirements we or our collaborators may not have anticipated. Such responses could lead to significant delays and increased costs in the development of our or our collaborated product candidates. In addition, because there may be approved treatments for some of the diseases for which we or our collaborators may seek approval, including vutrisiran for the treatment of ATTR amyloidosis with cardiomyopathy, or treatments in development which are approved by the time we or our collaborators file for approval, in order to receive regulatory approval, we or they may need to demonstrate through clinical trials that the product candidates we develop to treat these diseases are not only safe and effective, but safer and/or more effective than existing approved products. Interruption or delays in the operations of the FDA, EMA and comparable foreign regulatory agencies may impact the review, inspection and approval timelines for our or our collaborated product candidates. During the COVID-19 public health emergency, the FDA worked to ensure timely reviews of applications for medical products in line with its user fee performance goals and conducted mission critical domestic and foreign inspections to ensure compliance of manufacturing facilities with FDA quality standards. In addition, during the COVID-19 public health emergency, a number of companies announced receipt of complete response
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letters due to the FDA’s inability to complete required inspections for their applications. In December 2020, the FDA issued a CRL regarding Novartis’ NDA for inclisiran, stating that the agency could not approve the NDA by the PDUFA action date due to unresolved facility inspection-related conditions. In July 2021, Novartis announced that the resubmission to the FDA of the inclisiran NDA to address the complete response letter was filed, and the FDA approved Leqvio (the trade name under which inclisiran is marketed in the U.S.) in December 2021. This delay in the approval of Leqvio resulted in delayed milestone and royalty revenue to us. Any similar interruption or delay by the FDA, EMA or comparable foreign regulatory authorities could have a material adverse effect on our or our collaborators’ efforts to obtain regulatory approval for our or our collaborators’ product candidates, which could have a material adverse effect on our business, prospects, operating results or financial condition. For instance, the FDA may request additional clinical or other data or information in connection with the regulatory review of our or our collaborators’ product candidates, including by issuing a complete response letter that may require that we or our collaborators submit additional clinical or other data or impose other conditions that must be met in order to secure final approval of our or our collaborators’ NDA applications, including potentially requiring a facility inspection. Even if such data and information are submitted, or any such inspection is completed, the FDA may ultimately decide that the NDA does not satisfy the criteria for approval.
Any delay or failure in obtaining required approvals for our product candidates or our collaborated product candidates could have a material adverse effect on our ability to generate revenues from any product candidate for which we or our collaborators may seek approval in the future. For example, as a result of the CRL from the FDA in response to our sNDA for patisiran as a treatment for ATTR amyloidosis with cardiomyopathy, our ability to generate product revenues for patisiran will be negatively impacted. Furthermore, any regulatory approval to market any product may be subject to limitations on the approved uses for which we or our collaborators may market the product or the labeling or other restrictions, which could limit each such product’s market opportunity and have a negative impact on our business, prospects, operating results and financial condition and our stock price. In addition, the FDA has the authority to require a Risk Evaluation and Mitigation Strategy, or REMS, plan as part of its review of an NDA, or after approval, which may impose further requirements or restrictions on the distribution or use of an approved drug, such as limiting prescribing to certain physicians or medical centers that have undergone specialized training, limiting treatment to patients who meet certain safe-use criteria and requiring treated patients to enroll in a registry. In the EU, we or our collaborators could be required to adopt a similar plan, known as a risk management plan, and our products could be subject to specific risk minimization measures, such as restrictions on prescription and supply, the conduct of post-marketing safety or efficacy studies, or the distribution of patient and/or prescriber educational materials. In either instance, these limitations and restrictions may limit the size of the market for our products and affect reimbursement by third-party payors.
We are also subject to numerous foreign regulatory requirements governing, among other things, the conduct of clinical trials, manufacturing and marketing authorization, pricing and third-party reimbursement. The foreign regulatory approval process varies among countries and includes all of the risks associated with FDA approval described above as well as risks attributable to the satisfaction of local regulations in foreign jurisdictions. Approval by the FDA does not ensure approval by any regulatory authority outside the U.S. and vice versa.
Even if we or our collaborators obtain regulatory approvals, our marketed products will be subject to ongoing regulatory oversight. If we or our collaborators fail to comply with continuing U.S. and foreign requirements, our approvals could be limited or withdrawn, we could be subject to other penalties, and in any such case our business would be seriously harmed.
Following any initial regulatory approval of a product we or our collaborators may develop, including with respect to our four approved products, we will be subject to continuing regulatory oversight, including the review of adverse drug experiences and clinical results that are reported after our drug products are made commercially available. This includes results from any post-marketing tests or surveillance to monitor the safety and efficacy of our approved products or other products required as a condition of approval or otherwise agreed to by us. The regulatory approvals that we receive for ONPATTRO, AMVUTTRA, GIVLAARI and OXLUMO, as well as any regulatory approvals we receive for any of our product candidates, may also be subject to limitations on the approved uses for which the product may be marketed, including any expanded label for AMVUTTRA. Other ongoing regulatory requirements include, among other things, submissions of safety and other post-marketing information and reports, registration and listing, as well as continued compliance with good practice quality guidelines and regulations, including cGMP requirements and GCP requirements for any clinical trials that we conduct post-approval. In addition, we are conducting, and intend to continue to conduct, clinical trials for our product candidates, and we intend to seek approval to market our product candidates, in jurisdictions outside of the U.S., and therefore will be subject to, and must comply with, regulatory requirements in those jurisdictions.
The FDA has significant post-market authority, including, for example, the authority to require labeling changes based on new safety information and to require post-market studies or clinical trials to evaluate serious safety risks related to the use of a product and to require withdrawal of the product from the market. The FDA also has the authority to require a REMS plan after approval, which may impose further requirements or restrictions on the distribution or use of an approved product. As our approved products are used commercially, we or others could identify previously unknown side effects or known side effects could be observed as being more frequent or severe than in clinical trials or earlier post-marketing periods, in which case:
sales of our approved products may be lower than originally anticipated;
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regulatory approvals for our approved products may be restricted or withdrawn;
we may decide, or be required, to send product warning letters or field alerts to physicians, pharmacists and hospitals;
additional nonclinical studies or clinical trials, changes in labeling, adoption of a REMS plan, or changes to manufacturing processes, specifications and/or facilities may be required; and/or
government investigations or lawsuits, including class action suits, may be brought against us.
Any of the above occurrences could reduce or eliminate sales of our approved products, increase our expenses and impair our ability to successfully commercialize one or more of these products.
The CMO and manufacturing facilities we use to make our approved products and certain of our current product candidates, including our Cambridge facility, our Norton facility, as well as facilities at Agilent and other CMOs, will also be subject to periodic review and inspection by the FDA and other regulatory agencies. For example, Agilent and our Cambridge-based facility were subject to regulatory inspection by the FDA and the EMA in connection with the review of our applications for regulatory approval for ONPATTRO and GIVLAARI, and may be subject to similar inspection in connection with any subsequent applications for regulatory approval of one or more of our products filed in other territories. The discovery of any new or previously unknown problems with our or our CMO’s manufacturing processes or facilities, may result in restrictions on CMO or facility or the products manufactured at such facility, including delay in approval or, in the future, withdrawal of the product from the market. For example, due to a routine inspection by the FDA at a CMO facility that resulted in a pending inspection classification, we amended our regulatory submission for vutrisiran for the treatment of hATTR-amyloidosis with polyneuropathy in adults, which delayed our PDUFA goal date and AMVUTTRA’s FDA approval. Although we have developed cGMP capabilities and processes for the manufacture of patisiran formulated bulk drug product for commercial use and in 2020 completed construction of our cGMP manufacturing facility in Norton, Massachusetts, for drug substance for clinical and, eventually, commercial use, we may not have the ability or capacity to manufacture material at a broader commercial scale in the future. We may manufacture clinical trial materials, or we may contract a third party to manufacture this material for us. Reliance on CMOs entails risks to which we would not be subject if we manufactured products ourselves, including reliance on the applicable CMO for regulatory compliance.
If we or our collaborators, CMOs or service providers fail to comply with applicable continuing regulatory requirements in the U.S. or foreign jurisdictions in which we seek to market our products, we or they may be subject to, among other things, fines, warning letters, holds on clinical trials, refusal by the FDA or foreign regulatory authorities to approve pending applications or supplements to approved applications, suspension or withdrawal of regulatory approval, product recalls and seizures, refusal to permit the import or export of products, operating restrictions, injunction, civil penalties and criminal prosecution.
We may incur significant liability if enforcement authorities allege or determine that we are engaging in commercial activities with respect to our unapproved product candidates or promoting our commercially approved products in a way that violates applicable regulations.
Physicians have the discretion to prescribe approved drug products for uses that are not described in the product’s labeling and that differ from those approved by the FDA or other applicable regulatory agencies. Off-label uses are common across medical specialties. Although the FDA and other regulatory agencies that approve drug products do not regulate a physician’s practice of medicine or choice of treatments, the FDA and other regulatory agencies regulate a manufacturer’s communications regarding off-label use and prohibit off-label promotion, as well as the dissemination of false or misleading labeling or promotional materials, including by their agents. Manufacturers and their agents may not promote drugs for off-label uses or provide information in the promotion of drug products that is not consistent with the approved labeling for those products. For example, we may not currently promote ONPATTRO or AMVUTTRA in the U.S. for use in any indications other than the treatment of hATTR amyloidosis with polyneuropathy in adults. The FDA and other regulatory and enforcement authorities actively enforce laws and regulations prohibiting promotion of off-label uses and the promotion of products for which marketing approval has not been obtained, and if in the future we are found to have improperly marketed or promoted any of our commercial products, we may be subject to a broad range of civil, administrative and criminal penalties, including injunctive relief related to such commercial products’ promotional activities, substantial fines or penalties, and other legal or equitable sanctions. Any adverse decision, finding, allegation, or exercise of enforcement or regulatory discretion could harm our business, prospects, operating results, and financial condition. Other internal or government investigations or legal or regulatory proceedings, including lawsuits brought by private litigants, may also follow as a consequence.
Notwithstanding regulations related to product promotion, the FDA and other regulatory authorities allow companies to engage in truthful, non-misleading and non-promotional scientific exchange concerning their products, and we intend to engage in medical education activities and communicate with healthcare providers in compliance with all applicable laws and regulatory guidance. Nonetheless, the FDA, other applicable regulatory authorities, competitors, and other third parties may take the position that we are not in compliance with such regulations, and if such non-compliance is proven, it could harm our reputation or divert financial and management resources from our core business, and would have a material adverse effect on our business, prospects, operating results or financial condition. Moreover, any threatened or actual government enforcement
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actions or lawsuits by third parties could also generate adverse publicity, which could decrease demand for our products and require that we devote substantial resources that otherwise could be used productively on other aspects of our business.
In addition to our medical education efforts, we also offer patient support services to assist patients receiving treatment with our commercially approved products. Manufacturers have increasingly become the focus of government investigation of patient support programs based on allegations that through such services illegal inducements are provided to physicians and/or patients, leading to improper utilization of government resources through Medicare, Medicaid and other government programs. Companies that are found to have violated laws such as the federal Anti-Kickback Statute and/or the federal False Claims Act, or FCA, face significant liability, including civil and administrative penalties, criminal sanctions, and potential exclusion from participation in government programs.
As described below, we remain focused on our global compliance program, which is designed to support the execution of these programs and activities in compliance with applicable laws.
Even if we or our collaborators receive regulatory approval to market our product candidates, the market may not be receptive to our product candidates upon their commercial introduction, which could adversely affect our business, prospects, operating results and financial condition.
The product candidates that we are developing are based upon relatively new technologies or therapeutic approaches, and our first product, ONPATTRO, was approved for commercial sale in August 2018. Key participants in pharmaceutical marketplaces, such as physicians, third-party payors and consumers, may not accept a product intended to improve therapeutic results based on RNAi technology. As a result, it may be more difficult for us to convince the medical community and third-party payors to accept and use our products, or to provide favorable reimbursement.
Other factors we believe will materially affect market acceptance of our products include:
the timing of our receipt of any marketing approvals, the terms of any approvals and the countries in which approvals are obtained;
the safety and efficacy of our product candidates, as demonstrated in clinical trials and as compared with alternative treatments, if any;
relative convenience, dosing regimen and ease of administration of our product candidates;
the willingness of patients to accept potentially new routes of administration or new or different therapeutic approaches and mechanisms of action;
the success of our physician education programs;
the availability of adequate government and third-party payor reimbursement;
the pricing of our products, particularly as compared to alternative treatments, and the market perception of such prices and any price increase that we may implement in the future; and
availability of alternative effective treatments for the diseases that our product candidates we develop are intended to treat and the relative risks, benefits and costs of those treatments.
For example, ONPATTRO utilizes an intravenous mode of administration with pre-medication that physicians and/or patients may not readily adopt, and which may not compete favorably with other available options for the treatment of hATTR amyloidosis with polyneuropathy in adults, including WAINUA (eplontersen), which is marketed by AstraZeneca and Ionis, and administered subcutaneously, or tafamidis, which is marketed by Pfizer in several countries in pill form. In addition, fitusiran represents a new approach to treating hemophilia, which may not be readily accepted by physicians and patients and their caregivers. Vutrisiran, if approved for the treatment of ATTR amyloidosis with cardiomyopathy, could face similar challenges in market acceptance.
We are a multi-product commercial company and expect to continue to invest significant financial and management resources to continue to build our marketing, sales, market access and distribution capabilities and further establish our global infrastructure. If we are not able to continue to develop and scale these capabilities, we may not be able to successfully commercialize our current and any future products.
We received our first product approval in August 2018 and have established capabilities for marketing, sales, market access and distribution over the last several years. We currently expect to rely on third parties to launch and market certain of our product candidates in certain geographies, if approved. However, we are commercializing ONPATTRO, AMVUTTRA, GIVLAARI and OXLUMO, and intend to commercialize other product candidates, if approved, on our own globally in major markets. Accordingly, we have developed internal marketing, sales, market access and distribution capabilities as part of our core product strategy initially in the U.S., Europe and Japan, with expansion ongoing globally, which has required, and will continue to require, significant financial and management resources. For those products for which we will perform marketing, sales, market access and distribution functions ourselves, including ONPATTRO, AMVUTTRA, GIVLAARI and OXLUMO,
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and for future products we successfully develop with respect to which we retain development and commercialization rights, we could face a number of additional risks, including:
scaling and retaining our global sales, marketing and administrative infrastructure and capabilities;
hiring, training, managing and supervising our personnel worldwide;
the cost of further developing, or leveraging an established, marketing or sales force, which may not be justifiable in light of the revenues generated by any particular product and/or in any specific geographic region; and
our direct sales and marketing efforts may not be successful.
If we are unable to continue to develop and scale our own global marketing, sales, market access and distribution capabilities for our current and any future products, we will not be able to successfully commercialize our products without reliance on third parties.
The patient populations suffering from hATTR amyloidosis with polyneuropathy, ATTR amyloidosis with cardiomyopathy, AHP and PH1 have not been established with precision. If the actual number of patients suffering from these diseases is smaller than we estimate, or if we fail to raise awareness of these diseases and diagnosis is not improved, our business, prospects, operating results and financial condition may be adversely affected.
Our estimates regarding the potential market size for ONPATTRO, AMVUTTRA, GIVLAARI, OXLUMO or any future products at the time we commence commercialization, may be materially different from the actual market size, including as a result of the indication approved by regulatory authorities, which could result in significant changes in our business plan and may have a material adverse effect on our business, prospects, operating results and financial condition. If we are unable to successfully raise awareness of these diseases and improve diagnosis, it could have a material adverse effect on our business, prospects, operating results or financial condition, and it will be more difficult or impossible to achieve profitability.
Any products we currently market or may develop in the future may become subject to unfavorable pricing regulations, third-party reimbursement practices or healthcare reform initiatives, thereby harming our business, prospects, operating results and financial condition.
The regulations that govern marketing approvals, coverage, pricing and reimbursement for new drugs vary widely from country to country and are subject to change. Some countries require approval of the sale price of a drug before it can be marketed. In many countries, the pricing review period begins after marketing authorization or product licensing approval is granted. In some foreign markets, prescription pharmaceutical pricing remains subject to continuing governmental control even after initial approval is granted. We are actively monitoring these regulations as we market and sell our approved products and as several of our product candidates move through late stages of development. However, a number of our product candidates are currently in the earlier stages of development, and we will not be able to assess the impact of such regulations or any changes to such development programs for a number of years. We might also obtain regulatory approval for a product, including one or more of our approved products, in a particular country, but then be subject to price regulations or price controls that delay our commercial launch of the product and/or negatively impact the revenues we are able to generate from the sale of the product in that country and potentially in other countries due to reference pricing.
We believe that the efforts of governments and third-party payors to contain or reduce the cost of healthcare and legislative and regulatory proposals to broaden the availability of healthcare will continue to affect the business and financial condition of pharmaceutical and biopharmaceutical companies. In the U.S., pharmaceutical pricing is subject to both government and public scrutiny and calls for reform, and the U.S. government has continued to focus on legislative and regulatory changes designed to control costs. Specifically, there have been several recent U.S. Congressional inquiries into prescription drugs, and proposed and enacted federal and state legislation and regulations designed to, among other things, bring more transparency to drug pricing, reduce the cost of prescription drugs under Medicare, review the relationship between pricing and manufacturer patient programs, and reform government program reimbursement methodologies for drugs. These developments could, directly or indirectly, affect our ability to sell ONPATTRO, AMVUTTRA, GIVLAARI, OXLUMO or future products, if approved, at a favorable price.
At the federal level, for example, the Inflation Reduction Act, or IRA, includes several provisions that will impact our business to varying degrees. For example, the IRA may require us to pay rebates if we increase the cost of a Medicare Part B or Part D drug faster than the rate of inflation. In addition, our cost-sharing responsibility for any approved product covered by Medicare Part D could be significantly greater under the newly designed Part D benefit structure compared to the pre-IRA benefit design. Under the IRA’s Price Negotiation Program, an FDA approval for vutrisiran for treatment of Stargardt Disease would cause us to lose the orphan exemption for AMVUTTRA from Medicare price negotiation. As a result, in October 2022, we announced we would not pursue a Phase 3 clinical trial to study vutrisiran for the treatment of Stargardt Disease. Manufacturers that fail to comply with the IRA may be subject to various penalties, including civil monetary penalties or a potential excise tax. The effect of the IRA on our business and the healthcare industry in general continues to develop and may have additional adverse impacts on our company or our industry. The IRA is anticipated to have significant effects on the
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pharmaceutical industry and may reduce the prices we can charge and reimbursement we can receive for our products, among other effects.
Furthermore, the Biden administration has indicated that lowering prescription drug prices is a priority, but we do not know the impact of policies established by the Biden administration to lower the prices of prescription drug prices. For example, the Center for Medicare and Medicaid Innovation is developing new models intended to lower drug costs under Medicare and Medicaid, including designing new payment methods for drugs approved via FDA’s accelerated approval pathway, creating a list of generic drugs for which the out-of-pocket Part D costs will be capped at $2 a month per drug, and establishing new approach for administering outcomes-based agreements for cell and gene therapies. We do not know what additional steps the Biden administration may take to attempt to lower prescription drug prices or the impact of such steps. Although a number of these and other proposed measures may require authorization through additional legislation to become effective, and the current U.S. presidential administration may reverse or otherwise change these measures, both the current U.S. presidential administration and Congress have indicated that they will continue to seek new measures to control drug costs.
At the state level, governments have become increasingly aggressive in passing legislation and implementing regulations designed to control pharmaceutical product pricing. Some of these measures include restricting price, reimbursement, discounts, product access, and marketing; imposing drug price, cost, and marketing disclosure and transparency requirements; permitting importation from other countries; and encouraging bulk purchasing. For example, on January 5, 2024, the FDA authorized Florida’s Agency for Health Care Administration’s drug importation proposal, the first step toward Florida facilitating importation of certain prescription drugs from Canada. Importation of drugs from Canada and the Most Favored Nation, or MFN, Model may materially and adversely affect the price we receive for any of our commercially approved products. In addition, regional healthcare authorities and individual hospitals are increasingly using bidding procedures to determine what pharmaceutical products and which suppliers will be included in their prescription drug and other healthcare programs. These measures could reduce the ultimate demand for our products, once approved, or put pressure on our product pricing. We cannot predict what healthcare reform initiatives may be adopted in the future in the U.S. or other foreign countries. Further federal, state and foreign legislative and regulatory developments are likely, and we expect ongoing initiatives in the U.S. to increase pressure on drug pricing. Such reforms could have a material and adverse effect on our anticipated revenues from one or more of our approved products or other product candidates that we may successfully develop and for which we may obtain regulatory approval and may affect our business, prospects, operating results and financial condition and our ability to develop drug candidates.
Our ability to commercialize our approved products or any future products successfully also will depend in part on the extent to which coverage and reimbursement for these products and related treatments will be available from third-party payors such as government health administration authorities, private health insurers and other organizations. One or more of our approved products and any other products for which we are able to obtain marketing approval may not be considered medically necessary or cost-effective, and the amount reimbursed may be insufficient to allow us to sell such product(s) or any future products on a competitive basis or realize an appropriate return on our investment in product development. There may be significant delays in obtaining coverage for newly approved drugs, and coverage may be more limited than the purposes for which the drug is approved by the FDA or foreign regulatory authorities. Moreover, eligibility for coverage does not imply that any drug will be reimbursed in all cases or at a rate that covers our costs, including research, development, manufacture, sale and distribution or that covers a particular provider’s cost of acquiring the product. Interim payments for new drugs, if applicable, may also not be sufficient to cover our costs and may not be made permanent. Reimbursement may be based on lower-cost drugs that are already marketed, covered, and reimbursed, may be incorporated into existing payments for other services, and may reflect budgetary constraints or imperfections in data. Net prices for drugs may be reduced by mandatory discounts or rebates required by government healthcare programs or private payors and by any future relaxation of laws that presently restrict imports of drugs from countries where they may be sold at lower prices than in the U.S. In particular, governments in certain markets such as in EU, the U.K., Japan, and China, provide healthcare at low (or zero) direct costs to consumers at the point of care, and thus have significant power as large single payers to regulate prices or impose other cost control mechanisms. In addition, the emphasis on managed care in the U.S. has increased and we expect will continue to exert downward pressure on pharmaceutical pricing. Coverage policies, third-party reimbursement rates and pharmaceutical pricing regulations may change at any time. Even if favorable coverage and reimbursement status is attained for one or more products for which we receive regulatory approval, less favorable coverage policies and reimbursement rates may be implemented in the future.
Increasingly, the third-party payors who reimburse patients or healthcare providers, such as government and private insurance plans, are requiring that drug companies provide them with predetermined discounts from list prices, and are seeking to reduce the prices charged or the amounts reimbursed for drug products. In the U.S., we have entered into over 40 value-based agreements, or VBAs, and are negotiating additional VBAs with commercial health insurers. The goal of these agreements is to ensure that we are paid based on the ability of our commercially approved products to deliver results in the real world setting comparable to those demonstrated in our clinical trials, and the agreements are structured to link the performance of our approved products in real-world use to financial terms. Partnering with payors on these agreements is also intended to provide more confidence regarding the value of our products and help accelerate coverage decisions for patients. If the payment we receive for our products, or the reimbursement provided for such products, is inadequate in light of our significant development
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and other costs, or if reimbursement is denied, our return on investment could be adversely affected. In addition, we have stated publicly that we intend to grow through continued scientific innovation rather than arbitrary price increases. Specifically, we have stated that we will not raise the price of any product for which we receive marketing approval over the rate of inflation, as determined by the consumer price index for urban consumers (approximately 3.5% currently) absent a significant value driver. Our patient access philosophy could also negatively impact the revenues we are able to generate from the sale of one or more of our products in the future.
Insurers are increasingly adopting programs and policies that limit access to medications and increase out-of-pocket costs for patients. In the U.S., to help patients access and afford our approved product(s), we may utilize programs to assist them, including patient assistance programs and co-pay coupon programs for eligible patients. It is possible that changes in insurer policies regarding co-pay coupons (such as co-pay accumulator and maximizer programs) and patient assistance programs (such as alternative funding programs) and/or the introduction and enactment of new legislation or regulatory action could restrict or otherwise negatively affect these co-pay coupon programs and patient support programs, which could result in fewer patients using affected products, and therefore could have a material adverse effect on our sales, business, and financial condition.
We are subject to U.S. and certain foreign export and import controls, sanctions, embargoes, anti-corruption laws, and anti-money laundering laws and regulations. Failure to comply with these legal standards could impair our ability to compete in domestic and international markets. We can face criminal liability and other serious consequences for violations, which can harm our business.
We are subject to export control and import laws and regulations, including the U.S. Export Administration Regulations, U.S. Customs regulations, various economic and trade sanctions regulations administered by the U.S. Treasury Department’s Office of Foreign Assets Control, and anti-corruption laws, including the U.S. Foreign Corrupt Practices Act of 1977, as amended, the U.S. domestic bribery statute contained in 18 U.S.C. § 201, the U.S. Travel Act, the USA PATRIOT Act, the UK Bribery Act 2010, and other applicable anti-bribery and anti-money laundering laws. Anti-corruption laws are interpreted broadly and prohibit companies and their officers, directors, employees, agents, contractors, and other third-party representatives from directly or indirectly authorizing, promising, offering, providing, soliciting, or receiving payments or anything else of value in order to improperly influence the acts or decisions of recipients in the public or private sector or to secure any other improper advantage to obtain or retain business. From time to time, we may engage third parties to conduct clinical trials outside of the U.S., to sell our products abroad, and/or to obtain necessary permits, licenses, patent registrations, and other regulatory approvals. We have direct or indirect interactions with officials and employees of government agencies or government-affiliated hospitals, universities, and other organizations. We can be held liable for the corrupt or other illegal activities of agents, contractors, and third-party representatives acting on our behalf, even if we do not explicitly authorize or have actual knowledge of such activities. Any violations of the laws and regulations described above may result in substantial fines and penalties, reputational harm, and other adverse consequences.
We remain focused on these laws and the activities they regulate and maintain a global compliance program designed to empower our business to operate in compliance with their requirements.
Governments outside the U.S. may impose strict price controls, which may adversely affect our revenues.
The pricing of prescription pharmaceuticals is also subject to governmental control outside the U.S. In these countries, pricing negotiations with governmental authorities can take considerable time after the receipt of regulatory approval for a product. To obtain reimbursement or pricing approval in some countries, we may be required to conduct a clinical trial that compares the cost-effectiveness of our product candidates to other available therapies, which is time-consuming and costly. If reimbursement of our products is unavailable or limited in scope or amount, or if pricing is set at unsatisfactory levels, our ability to generate revenues and become profitable could be impaired.
In some countries, including Member States of the EU, or Japan, the pricing of prescription drugs may be subject to governmental control. Additional countries may adopt similar approaches to the pricing of prescription drugs. In such countries, pricing negotiations with governmental authorities can take considerable time after receipt of regulatory approval for a product. In addition, governments and other stakeholders can put considerable pressure on prices and reimbursement levels, including as part of cost containment measures. Moreover, political, economic and regulatory developments may further complicate pricing negotiations, and pricing negotiations may continue after coverage and reimbursement have been obtained. Reference pricing used by various countries and parallel distribution, or arbitrage between low-priced and high-priced countries, can further reduce prices. We cannot be sure that such prices and reimbursement will be acceptable to us or our collaborators. Publication of discounts by third-party payors or authorities may lead to further pressure on the prices or reimbursement levels within the country of publication and other countries. If pricing is set at unsatisfactory levels or if reimbursement of our products is unavailable or limited in scope or amount, our revenues from sales by us or our collaborators and the potential profitability of our approved products or any future products in those countries would be negatively affected. We could also suffer impact from tightening pricing controls on account of greater competition from less expensive generic or biosimilar products once patent or other exclusivity expires. Certain governments have adopted policies to switch prescribed products to generic versions to reduce costs.
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If we or our collaborators, CMOs or service providers fail to comply with healthcare laws and regulations, or legal obligations related to privacy, data protection and information security, we or they could be subject to enforcement actions, which could negatively impact our ability to develop, market and sell our products and may harm our reputation.
Healthcare providers, physicians, and third-party payors play a primary role in the recommendation and prescription of any products for which we obtain marketing approval. Our existing and future arrangements with third-party payors and customers may expose us to broadly applicable fraud and abuse and other healthcare laws and regulations that may constrain our business or financial arrangements and relationships through which we market, sell, and distribute our products. Restrictions under applicable federal and state healthcare laws and regulations include the following:
The U.S. federal Anti-Kickback Statute, which prohibits, among other things, persons or entities from knowingly and willfully soliciting, receiving, offering or paying any remuneration (including any kickback, bribe or rebate), directly or indirectly, overtly or covertly, in cash or in kind, to induce, or in return for, the purchase, lease, order, arrangement, or recommendation of any good, facility, item or service for which payment may be made, in whole or in part, under a federal healthcare program, such as the Medicare and Medicaid programs. A person or entity does not need to have actual knowledge of the federal Anti-Kickback Statute or specific intent to violate it to have committed a violation. Violations are subject to civil and criminal fines and penalties, imprisonment, and exclusion from government healthcare programs. In addition, the government may assert that a claim including items or services resulting from a violation of the federal Anti-Kickback Statute constitutes a false or fraudulent claim for purposes of the federal FCA or federal civil money penalties.
The U.S. federal false claims laws, including the FCA, which prohibit, among other things, individuals or entities from knowingly presenting or causing to be presented, claims for payment by government-funded programs such as Medicare or Medicaid that are false or fraudulent, making, using or causing to be made or used a false record or statement material to a false or fraudulent claim to the federal government, or making a false statement to avoid, decrease or conceal an obligation to pay money to the federal government. Manufacturers can be held liable under the FCA even when they do not submit claims directly to government payors if they are deemed to “cause” the submission of false or fraudulent claims. The FCA also permits a private individual acting as a “whistleblower” to bring actions on behalf of the federal government alleging violations of the FCA and to share in any monetary recovery. Penalties are three times the amount of the claims in question plus civil monetary penalties.
The federal civil monetary penalties laws, which impose civil fines for, among other things, the offering or transfer of remuneration to a Medicare or Medicaid beneficiary if the person knows or should know it is likely to influence the beneficiary’s selection of a particular provider, practitioner, or supplier of services reimbursable by Medicare or Medicaid, unless an exception applies.
The federal Health Insurance Portability and Accountability Act of 1996, or HIPAA, which created, among other provisions, federal criminal statutes that prohibit knowingly and willfully executing, or attempting to execute, a scheme to defraud any healthcare benefit program or obtain, by means of false or fraudulent pretenses, representations, or promises, any of the money or property owned by, or under the custody or control of, any healthcare benefit program, regardless of the payor (e.g., public or private) and, in any matter involving a health care benefit program, knowingly and willfully falsifying, concealing or covering up by any trick or device a material fact or making any materially false statements in connection with the delivery of, or payment for, healthcare benefits, items or services. Similar to the federal Anti-Kickback Statute, a person or entity can be found guilty of violating HIPAA without actual knowledge of the statute or specific intent to violate it.
HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act, including its implementing regulations, which impose requirements relating to the privacy, security, and transmission of individually identifiable health information; and requires notification to affected individuals and regulatory authorities of certain breaches of security of individually identifiable health information.
Federal “sunshine” requirements imposed by the Affordable Care Act on drug, device, biological and medical supply manufacturers when payment is available under Medicare, Medicaid or the Children’s Health Insurance Program (with certain exceptions) to report annually to Health and Human Services under the Open Payments Program, information regarding any payment or other “transfer of value” made or distributed to physicians (defined to include doctors, dentists, optometrists, podiatrists and chiropractors), certain non-physician providers such as physician assistants and nurse practitioners, and teaching hospitals, as well as ownership and investment interests held by physicians and their immediate family members. Failure to submit timely, accurate and complete information may result in civil monetary penalties.
Federal price reporting laws, which require manufacturers to calculate and report complex pricing metrics to government programs, where such reported prices may be used in the calculation of reimbursement and/or discounts on approved products.
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Federal statutory and regulatory requirements applicable to pricing and sales of products to federal government agencies.
Federal consumer protection and unfair competition laws, which broadly regulate marketplace activities and activities that potentially harm consumers.
State and foreign laws comparable to each of the above federal laws, including in the EU laws prohibiting giving healthcare professionals any gift or benefit in kind as an inducement to prescribe our products, national transparency laws requiring the public disclosure of payments made to healthcare professionals and institutions, and data privacy laws, in addition to anti-kickback and false claims laws applicable to commercial insurers and other non-federal payors, requirements for mandatory corporate regulatory compliance programs, and laws relating to government reimbursement programs, patient data privacy and security.
European privacy laws including Regulation 2016/679, known as the General Data Protection Regulation, or the EU GDPR, and the EU GDPR as transposed into the laws of the UK, the UK GDPR, collectively referred to as the GDPR, and the e-Privacy Directive (2002/58/EC), and the national laws implementing each of them, as well as the Public and Electronic Communications Regulations 2003 in the UK and the privacy laws of Japan, Brazil and other territories.
The California Consumer Privacy Act of 2018, as amended by the California Privacy Rights Act of 2020, or, collectively, the CCPA, that, among other provisions, gives California residents rights of access, correction, portability, and deletion of their personal information and various opt out rights. The CCPA also imposes various obligations on regulated businesses, such as to maintain privacy notices, implement reasonable security practices, and include specific terms in contracts with data processors. The CCPA also created a new state agency that is vested with authority to implement (including through rule making) and enforce the CCPA. The CCPA provides for civil penalties for violations, as well as a limited private right of action for data breaches.
Furthermore, comprehensive privacy laws similar to the CCPA have been enacted in more than ten other states and proposed in several others. Three states have additionally enacted laws regulating “consumer health data,” which impose additional obligations on regulated entities beyond state comprehensive privacy laws, such as to obtain distinct consents for certain collection and sharing of consumer health data, obtain authorization to sell consumer health data, and maintain a consumer health data privacy policy. Washington’s law regulating consumer health data contains a private right of action. The effects of the CCPA and other state privacy laws are potentially significant and may require us to modify our data collection or processing practices and policies and to incur substantial costs and expenses in an effort to comply and increase our potential exposure to regulatory enforcement and/or litigation.
Some state laws also require pharmaceutical manufacturers to comply with the pharmaceutical industry’s voluntary compliance guidelines and the relevant compliance guidance promulgated by the federal government, in addition to requiring manufacturers to report information related to payments to physicians and other healthcare providers or marketing expenditures and pricing information. State and foreign laws also govern the privacy and security of health information, many of which differ from each other in significant ways and often are not preempted by HIPAA, thus complicating our compliance efforts.
If our operations are found to be in violation of any of the aforementioned requirements, we may be subject to penalties, including civil or criminal penalties (including individual imprisonment), criminal prosecution, monetary damages, the curtailment or restructuring of our operations, or exclusion from participation in government contracting, healthcare reimbursement or other government programs, including Medicare and Medicaid, or the imposition of a corporate integrity agreement with the Office of Inspector General of the Department of Health and Human Services, or the OIG, any of which could materially and adversely affect our business, prospects, operating results or financial condition. We remain focused on enhancing our global compliance infrastructure following the commercial launch of our four products over the last four years in the U.S., EU and multiple other geographies, and as we prepare for the launch of our products in additional countries, assuming regulatory approvals. Although effective compliance programs can mitigate the risk of investigation and prosecution for violations of these laws, these risks cannot be entirely eliminated. For additional information, see the Risk Factor captioned “We may incur significant liability if enforcement authorities allege or determine that we are engaging in commercial activities with respect to our unapproved product candidates or promoting our commercially approved products in a way that violates applicable regulations.” Any action against us for an alleged or suspected violation could cause us to incur significant legal expenses and could divert our management’s attention from the operation of our business, even if our defense is successful. In addition, achieving and sustaining compliance with applicable laws and regulations may be costly to us in terms of money, time and resources.
If we or our collaborators, CMOs or service providers fail to comply with applicable federal, state or foreign laws or regulations, we could be subject to enforcement actions, which could affect our ability to develop, market and sell our approved products, or any future products, successfully and could harm our reputation and lead to reduced acceptance of our products by the market. These enforcement actions include, among others, civil and criminal penalties, up to and including criminal prosecution resulting in fines, exclusion from healthcare reimbursement programs and imprisonment.
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Moreover, federal, state and foreign laws or regulations are subject to change, and while we, our collaborators, CMOs and/or service providers currently may be compliant, we could fall out of compliance due to changes in interpretation, prevailing industry standards or the legal structure.
Third party patient assistance programs that receive financial support from companies have become the subject of enhanced government and regulatory scrutiny. The OIG has established guidelines that suggest that it is lawful for pharmaceutical manufacturers to make donations to charitable organizations who provide co-pay assistance to Medicare patients, provided that such organizations, among other things, are bona fide charities, are entirely independent of and not controlled by the manufacturer, provide aid to applicants on a first-come basis according to consistent financial criteria and do not link aid to use of a donor’s product. However, donations to patient assistance programs have received negative publicity and have been the subject of multiple government enforcement actions, related to allegations regarding their use to promote branded pharmaceutical products over other less costly alternatives. Specifically, in recent years, there have been multiple settlements resulting from government claims challenging the legality of patient assistance programs under a variety of federal and state laws. We have made and may continue to make grants to independent charitable foundations that help financially needy patients with their premium, co-pay, and co-insurance obligations. If we do so, and if we or our donation recipients are deemed to be acting in violation of relevant laws, regulations or evolving government guidance, we could be subject to damages, fines, penalties, or other criminal, civil, or administrative sanctions or enforcement actions.
We are subject to governmental regulation and other legal obligations related to privacy, data protection and information security, and we are subject to consumer protection laws that regulate our marketing practices and prohibit unfair or deceptive acts or practices. Our actual or perceived failure to comply with such obligations could harm our business.
The GDPR imposes strict requirements on controllers and processors of personal data, including special protections for “special category data,” which includes health, biometric and genetic information of data subjects located in the EEA and UK. Further, GDPR provides a broad right for EEA Member States to create supplemental national laws, such as laws relating to the processing of health, genetic and biometric data, which could further limit our ability to use and share such data or could cause our costs to increase, and harm our business and financial condition.
Failure to comply with the requirements of the GDPR and the related national data protection laws of the EEA Member States and the UK, which may deviate slightly from the GDPR, may result in fines of up to 4% of total global annual revenue, or €20.0 million (₤17.5 million under the UK GDPR), whichever is greater, and in addition to such fines, we may be the subject of litigation and/or adverse publicity, which could have a material adverse effect on our reputation and business. As a result of the implementation of the GDPR, we are required to implement a number of measures to ensure compliance with the data protection regime. The GDPR (i) requires us to inform data subjects of how we process their personal data and how they can exercise their rights, (ii) requires us to ensure we have a valid legal basis to process personal data (if this is consent, the requirements for obtaining consent carries a higher threshold), (iii) requires us to appoint a data protection officer where sensitive personal data (i.e., health data) is processed on a large scale, (iv) introduces mandatory data breach notification requirements throughout the EEA and UK, (v) requires us to maintain records of our processing activities and document data protection impact assessments where there is high risk processing, (vi) imposes additional obligations on us when we are contracting with service providers, requires (vii) appropriate technical and organizational measures to be put in place to safeguard personal data and (viii) requires us to adopt appropriate privacy governance including policies, procedures, training and data audit.
Significantly, the GDPR imposes strict rules on the transfer of personal data out of the EEA and UK to the U.S. or other regions that have not been deemed to offer “adequate” privacy protections. In the past, companies in the U.S. were able to rely upon the EU-U.S., UK-U.S. and the Swiss-U.S. Privacy Shield frameworks as a basis for lawful transfer of personal data from the EU and the UK to the U.S. In July 2020, the Court of Justice of the European Union, or CJEU, in Case C-311/18 (Data Protection Commissioner v Facebook Ireland and Maximillian Schrems, or Schrems II) invalidated the EU-U.S. Privacy Shield on the grounds that the Privacy Shield failed to offer adequate protections to EU personal data transferred to the U.S. The CJEU, in the same decision, deemed that the Standard Contractual Clauses, or SCCs, published by the EC are valid. However, the CJEU ruled that transfers made pursuant to the SCCs need to be assessed on a case-by-case basis to ensure the law in the recipient country provides “essentially equivalent” protections to safeguard the transferred personal data as the EU, and required businesses to adopt supplementary measures if such standard is not met. Subsequent guidance published by the European Data Protection Board, or EDPB, in June 2021 described what such supplementary measures must be, and stated that businesses should avoid or cease transfers of personal data if, in the absence of supplementary measures, equivalent protections cannot be afforded. On June 4, 2021, the EC published new versions of the SCCs, which seek to address the issues identified by the CJEU’s Schrems II decision and provide further details regarding the transfer assessments that the parties are required to conduct when implementing the new SCCs. However, there continue to be concerns about whether the SCCs and other mechanisms will face additional challenges. Similarly, in September 2020, the Swiss data protection authority determined the Swiss-U.S. Privacy Shield framework was no longer a valid mechanism for Swiss-U.S. data transfers and raised questions about the validity of the SCCs as a mechanism for transferring personal data from Switzerland. While SCCs provide an alternative to our Privacy Shield certification for EU-U.S. data flows, the decision (and certain regulatory guidance issued in its wake) casts doubt on the legality of EU-U.S. data flows in general. Any inability to transfer, or burdensome restrictions on the
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ability to transfer, personal data from the EU to the U.S. in compliance with applicable data protection laws may impede our ability to conduct clinical trials and may adversely affect our business, prospects, operating results and financial condition. The UK is not subject to the EC’s new SCCs but has published its own transfer mechanism, the International Data Transfer Agreement or International Data Transfer Addendum, which enables transfers from the UK. On March 25, 2022, the EC and the U.S. announced a political agreement on a new “Trans-Atlantic Data Privacy Framework” to replace the invalidated Privacy Shield. The framework introduced new binding safeguards to address the concerns raised by the CJEU in Schrems II. On July 10, 2023, the EC announced that it had adopted its adequacy decision for that data privacy framework, labelled the EU-U.S. Data Privacy Framework. The adequacy decision concluded that the U.S. ensures an adequate level of protection for personal data transferred from the EU to US companies under the new framework, and the EC stated that as a result personal data can flow safely from the EU to US companies participating in the framework, without having to put in place additional data protection safeguards. The EU-U.S. Data Privacy Framework is subject to periodic reviews, to be conducted by the EC, together with other European data protection authorities and U.S. authorities, with the first review to take place within a year of adoption of the adequacy decision. A case has been lodged with and remains pending before the EU courts challenging the validity of the EU-U.S. Data Privacy Framework.
EEA Member States have adopted implementing national laws to implement the GDPR which may partially deviate from the GDPR and the competent authorities in the EEA Member States may interpret GDPR obligations slightly differently from country to country, and we do not expect to operate in a uniform legal landscape in the EU. In addition, the UK Government has now introduced a Data Protection and Digital Information Bill, or the UK Bill, into the UK legislative process. The aim of the UK Bill is to reform UK’s data protection regime following Brexit. If passed, the final version of the UK Bill may have the effect of further altering the similarities between the UK and EEA data protection regime. The anticipated UK general election in 2024 could postpone passage of the UK Bill.
我們受到當地數據保護主管機構的監督,這些監管適用於我們監控歐洲經濟區或英國個人行爲的司法轄區(即進行臨床試驗)。我們依賴許多第三方提供我們的服務,在其中許多處理歐盟和(或)英國個人的個人數據。對於每個這樣的提供者,我們將簽訂或計劃簽訂合同安排,根據這些安排,提供者有合同義務僅按照我們的指示處理個人數據,並進行或計劃開展盡職調查,以確保他們已經具備足夠的技術和組織安防-半導體措施。
我們還受到關於電子營銷和Cookie的不斷髮展的歐洲隱私法律的約束。歐盟正在替換電子隱私指令(2002/58/EC)爲一套新規則,採取一項法規的形式,將直接實施在每個歐洲成員國的法律中,無需進一步立法。雖然最初計劃在2018年5月25日(與GDPR一同)採納電子隱私法規,但目前仍在歐洲立法過程中。草案規定於2019年11月22日被歐盟理事會常駐代表委員會拒絕通過;目前還不清楚新規定將在何時,甚至是否被採納。我們還受到其他國家(如加拿大)當前和不斷髮展的隱私法律的約束。
爲遵守美國和國際數據保護法律法規,我們需在合同中承擔更多繁重義務,限制我們收集、使用和披露數據的能力,並在某些情況下影響我們在特定司法管轄區開展業務的能力。未遵守這些法律法規可能導致政府採取執法行動(可能包括民事、刑事和行政處罰)、私人訴訟,以及/或不利宣發,且可能對我們的運營結果和業務造成負面影響。此外,臨床試驗對象、僱員和我們或潛在合作伙伴獲取個人信息的其他個人,以及與我們分享這些信息的提供者,可能限制我們收集、使用和披露信息的能力。對我們侵犯個人隱私權、未遵守數據保護法律、或違反合同義務的指控,即使我們沒有被判有罪,可能會導致昂貴和耗時的辯護,並可能導致不利宣發,損害我們的業務。
我們從聯邦政府獲取服務、報銷或資金的能力可能會受到聯邦支出和服務可能減少的影響,若我們不能有效地適應這些變化,可能會極大地影響我們的業務、前景、運營結果和財務狀況。
根據2011年《預算控制法案》,國會未能在2013年至2021年間制定至少1.2萬億美元的赤字減少措施,將觸發對大多數聯邦項目的自動削減。這些削減包括對醫療保險支付的整體降低,每財政年度最多降低2%,從2013年開始。其中一些自動削減已經實施,導致醫療保險支付給醫生、醫院和其他醫療保健提供者等方面的削減。根據修改法令的立法,包括2018年的《兩黨預算法案》,這些削減將持續到2030年,除非採取額外的國會行動。根據《冠狀病毒援助、救助和經濟安全法案》,以及隨後的立法,由於COVID-19大流行,這些削減從2020年5月1日至2021年12月31日暫停。在暫停後,從2022年4月1日開始,將實施1%的支付削減,持續到2022年6月30日。2%的支付削減將於2022年7月1日恢復。2012年《美國納稅人救濟法案》等法案減少了向多家提供者支付的醫療保險費用,並將政府追回提供者超支款項的時效限制期從三年延長到五年。這些新法律可能導致醫療保險和其他醫療保健資金額外減少,或以其他方式影響我們的批准產品或任何產品候選者的價格。
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我們可能獲得監管批准的頻率,或者我們的產品或任何未來產品被開具或使用的頻率。
國會此前採取的減少支出措施、國會在政府資金撥款水平上存在的分歧、政府債務高企,以及《醫療保險信託基金受託人》對於目前結構下節目可持續性的警告,表明有可能相關節目的資金不會得到不間斷/持續增長的保證。分配給聯邦撥款和合同的金額可能會被減少或取消。這些減少可能還會影響相關機構及時審查和批准藥物研發、製造業-半導體,以及市場推廣活動的能力,從而可能延遲我們開發、推出和銷售我們已獲批准的產品以及我們可能開發的其他產品。
如果我們未能遵守3400億美元藥物定價計劃或其他美國政府定價計劃下的義務,我們可能會面臨額外的補償要求、罰款、制裁和罰款,這可能會對我們的業務、前景、運營結果和財務狀況產生重大不利影響。
我們參與了3400億美元的藥品定價計劃、醫療補償計劃,以及美國的許多其他聯邦和州政府定價計劃,以便通過某些政府醫療保健計劃爲我們的產品獲得覆蓋。這些計劃通常要求我們在我們的產品發放給這些計劃的受益人時向某些支付方提供折扣或支付回扣。這些計劃還可能施加其他要求,包括某些價格報告要求。我們在這些政府定價計劃下的義務變更頻繁,而計劃要求通常含糊不清。如果我們未能遵守這些計劃下的義務,包括未能向政府提供及時準確的信息、支付正確的回扣或提供正確的折扣價格,我們可能會受到處罰。遵守這些計劃及對這些計劃的將來修改可能需要耗費大量資源,對我們的業務、前景、運營結果和財務狀況可能會產生重大不利影響。
我們的業務存在着重大的產品責任索賠風險。如果我們無法獲得足夠的保險,針對我們的產品責任索賠可能會對我們的業務、前景、運營結果和財務狀況產生不利影響。
我們的業務使我們面臨着由人類治療產品的開發、測試、製造和營銷所固有的重大潛在產品責任風險。產品責任索賠可能會延遲或阻止我們的臨床開發項目的完成。此類索賠可能無法完全由產品責任保險承擔。此外,產品責任索賠可能導致FDA對我們批准的產品、我們的製造工藝和設施或我們的營銷計劃的安全性和有效性進行調查,並可能召回我們的產品或採取更嚴重的執法行動,限制可使用的批准適應症,或暫停或撤銷批准。無論在法律上的依據還是最終結果如何,責任索賠還可能導致我們產品的需求量減少,損害我們的聲譽,增加捍衛相關訴訟的成本,分散管理層的時間和我們的資源,爲試驗參與者或患者提供大量的賠償款項,並導致我們的股價下跌。我們目前擁有我們認爲適合我們開發階段的產品責任保險,包括我們批准產品的營銷和銷售。我們擁有的任何保險或未來獲得的保險可能無法爲潛在責任提供足夠的賠償。此外,臨床試驗和產品責任保險的費用越來越昂貴。因此,我們可能無法以合理的成本獲得足夠的保險來保護我們免受可能對我們的業務產生重大不利影響的產品責任索賠造成的損失。
我們的員工可能會參與不端行爲或其他不當活動,包括違反監管標準和要求或內幕交易違規行爲,這可能會嚴重損害我們的業務、前景、營運結果和財務狀況。
我們面臨僱員欺詐或其他不當行爲的風險。員工的不當行爲可能包括故意違反政府法規,包括在美國和國外的醫療保健欺詐、濫用和反回扣法律法規,或者未能準確報告財務信息或數據,或者未向我們披露未經授權的活動。特別是,在醫療保健行業的銷售、營銷和業務安排受到廣泛的法律法規的約束,旨在防止欺詐、不當行爲、回扣、利益輸送和其他濫用行爲。正如「風險因素」所述,「如果我們或我們的合作伙伴、CMO或服務提供商未能遵守醫療保健法律法規或與隱私、數據保護和信息安全相關的法律義務,我們或他們可能受到執法行動的制裁,這可能會對我們開發、營銷和銷售產品的能力造成負面影響,並可能損害我們的聲譽」,這些法律和法規可能限制或禁止廣泛範圍的定價、折扣、營銷和促銷、銷售佣金、客戶激勵計劃和其他業務安排。員工不當行爲也可能涉及在臨床試驗過程中獲取的信息的錯誤使用,包括基於信息進行的不當交易,這可能導致監管制裁和嚴重損害我們的聲譽。我們建立了全球合規計劃,並致力於其不斷髮展和完善。我們的計劃包括風險評估和監控,營造鼓勵員工和第三方提出善意問題或關切的言論自由文化,以及明確的流程和系統來審查和整改指控和發現的潛在問題。然而,並不總是可能識別和阻止員工不當行爲,我們採取的預防措施可能無法有效控制未知或未管理的風險或損失,也無法保護我們免受政府調查或其他行動或訴訟的侵害
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因未能遵守這些法律或法規而導致的後果。如果對我們採取任何此類行動,並且我們未能成功捍衛自己的權利,這些行動可能會對我們的業務、前景、運營結果和財務狀況產生重大影響,包括徵收重罰款或其他制裁。
如果我們不遵守法律規定的環境保護、健康和人類安全保護,我們的業務、前景、經營業績和財務狀況可能會受到不利影響。
我們的研究、開發和製造涉及使用危險材料、化學品和各種放射性化合物。我們在劍橋和諾頓的設施中保有各種易燃和有毒化學品,這些化學品是我們研究、開發和製造活動所必需的。我們受聯邦、州和地方法律法規的約束,這些法律法規管理着這些危險材料的使用、製造、儲存、處理和處置。我們相信我們在劍橋和諾頓設施中用於儲存、處理和處置這些材料的程序符合劍橋市、諾頓鎮、麻省聯邦和勞工部職業安全衛生管理局的相關指導方針。儘管我們相信我們用於處理和處置這些材料的安全程序符合適用法規規定的標準,但無法消除這些材料導致意外污染或傷害的風險。如果發生事故,我們可能會因造成的損害承擔責任,可能會相當巨大。我們還受到許多環保、健康和職場安全法律法規的約束,包括規管實驗室程序、暴露於血源性病原體以及處理生物危險材料的法規。
儘管我們保留工傷賠償保險以覆蓋我們可能因員工受傷而產生的費用和支出,但這種保險可能無法提供充分的保障來應對潛在責任。我們不保留保險來應對可能因我們存儲或處理生物、危險或放射性材料而提出的環境責任或有毒侵權索賠。未來可能頒佈進一步影響我們業務的聯邦、州和地方法律法規。我們可能需要花費大量成本來遵守這些法律法規,並且如果違反任何其中之一,可能會被處以巨額罰款或處罰。
與專利、許可證和商業祕密相關的風險
如果我們無法獲得和執行對我們的發現的專利保護,我們開發和商業化產品候選人的能力將受到損害。
我們的成功在一定程度上取決於我們能夠根據美國和其他國家的專利和其他知識產權法保護我們開發的專有構成、方法和技術,從而防止他人非法使用我們的發明和專有信息。然而,我們可能無法持有製造和商業化我們擬議產品所需專利權。由於某些美國專利申請直到專利授權時仍保密,例如在2000年11月29日之前提交的申請,或在此日期之後提交的不會在外國提交的申請,第三方可能已經爲我們待批專利申請涵蓋的主題提交了申請,而我們可能不知道這些申請,我們的專利申請可能不會優先於這些申請。出於這個原因和其他原因,我們可能無法獲得所需的專利權,從而失去所需的獨家權。此外,我們或我們的合作伙伴可能需要根據第三方專利獲取許可,以營銷我們或我們合作伙伴的批准產品中的一個或多個產品,或進一步開發和商業化未來產品,或繼續由我們或我們的合作伙伴開發的流水線產品候選。如果我們無法獲得許可或不以合理條件獲得許可,我們或我們的許可方可能無法營銷受影響的產品或進行所需的活動。
我們的策略取決於我們快速識別和尋求對我們的發現進行專利保護的能力。此外,我們可能依賴第三方合作伙伴提交與我們共同開發的專有技術有關的專利申請。獲得專利保護的過程既昂貴又耗時。如果我們或我們現有或將來的合作伙伴未能以合理的成本和及時的方式提交和處理所有必要和理想的專利申請,我們的業務可能會受到不利影響。儘管我們和我們的合作伙伴努力保護我們的專有權益,未經授權的第三方可能會獲得並使用我們視爲專有的信息。儘管授予的專利被認爲是有效的,但這並不保證專利能夠抵禦有效性挑戰或被視爲可執行。我們獲得的任何專利,或者將來獲得的專利,都可能受到挑戰,無效,被判爲不可執行或被試圖規避我們知識產權的當事方所繞過。此外,第三方或美國專利商標局(USPTO)可能發起涉及我們專利或專利申請的干擾程序。對我們的專利或專利申請的任何挑戰,被判爲不可執行或無效,或繞過,都將是昂貴的,需要我們管理層大量的時間和精力,可能會減少或取消來自第三方許可方向我們的里程碑和/或版稅支付,且可能對我們的業務產生重大不利影響。
我們待定的專利申請可能不會導致已頒發的專利。藥品或生物技術公司,包括我們在內,專利地位普遍不確定,並涉及複雜的法律和事實考慮。美國專利商標局及其外國同行頒發專利所使用的標準並不總是可預測或統一地應用,並且可能會發生變化。類似地,生物技術發明在美國和外國將獲得的保護程度仍然不確定,並取決於專利局、法院和立法者決定的保護範圍。此外,美國國會和國際司法管轄區定期就
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modifying various aspects of patent law. For example, the America Invents Act, or AIA, included a number of changes to the patent laws of the U.S. If any of the enacted changes do not provide adequate protection for discoveries, including our ability to pursue infringers of our patents for substantial damages, our business could be adversely affected. One major provision of the AIA, which took effect in March 2013, changed U.S. patent practice from a first-to-invent to a first-to-file system. If we fail to file an invention before a competitor files on the same invention, we no longer have the ability to provide proof that we were in possession of the invention prior to the competitor’s filing date, and thus would not be able to obtain patent protection for our invention. There is also no uniform, worldwide policy regarding the subject matter and scope of claims granted or allowable in pharmaceutical or biotechnology patents.
Accordingly, we do not know the degree of future protection for our proprietary rights or the breadth of claims that will be allowed in any patents issued to us or to others. We also rely to a certain extent on trade secrets, know-how and technology, which are not protected by patents, to maintain our competitive position. If any trade secret, know-how or other technology not protected by a patent were to be disclosed to or independently developed by a competitor, our business, prospects, operating results and financial condition could be materially adversely affected.
Failure to obtain and maintain broad patent scope and all available regulatory exclusivities and to maximize patent term restoration or extension on patents covering our product candidates and products may lead to loss of exclusivity and generic entry resulting in a loss of market share and/or revenue.
We license patent rights from third-party owners. If such owners do not properly or successfully obtain, maintain or enforce the patents underlying such licenses, our competitive position and business, prospects, operating results and financial condition may be harmed.
We are a party to a number of licenses that give us rights to third-party intellectual property that is necessary or useful for our business. In particular, we have obtained licenses from, among others, Ionis, Arbutus, and Dicerna. We also intend to enter into additional licenses to third-party intellectual property in the future.
Our success will depend in part on the ability of our licensors to obtain, maintain and enforce patent protection for our licensed intellectual property, in particular, those patents to which we have secured exclusive rights. Our licensors may not successfully prosecute the patent applications we have licensed. Even if patents issue in respect of these patent applications, our licensors may fail to maintain these patents, may determine not to pursue litigation against other companies that are infringing these patents, or may pursue such litigation less aggressively than we would. Without protection for the intellectual property we license, other companies might be able to offer substantially identical products for sale, which could adversely affect our competitive business position and harm our business, prospects, operating results and financial condition. In addition, we sublicense our rights under various third-party licenses to our collaborators. Any impairment of these sublicensed rights could result in reduced revenues under our collaboration agreements or result in termination of an agreement by one or more of our collaborators.
Other companies or organizations may challenge our patent rights or may assert patent rights that prevent us from developing and commercializing our products.
RNAi is a relatively new scientific field, the commercial exploitation of which has resulted in many different patents and patent applications from organizations and individuals seeking to obtain patent protection in the field. We have obtained grants and issuances of RNAi patents and have licensed many of these patents from third parties on an exclusive basis. The issued patents and pending patent applications in the U.S. and in key markets around the world that we own or license claim many different methods, compositions and processes relating to the discovery, development, manufacture and commercialization of RNAi therapeutics.
Specifically, we have a portfolio of patents, patent applications and other intellectual property covering, among other things: fundamental aspects of the structure and uses of siRNAs, including their use as therapeutics, and RNAi-related mechanisms; chemical modifications to siRNAs that improve their suitability for therapeutic and other uses; siRNAs directed to specific targets as treatments for particular diseases; delivery technologies, such as in the fields of carbohydrate conjugates and cationic liposomes; and all aspects of our specific development candidates.
As the field of RNAi therapeutics is maturing, patent applications are being fully processed by national patent offices around the world. There is uncertainty about which patents will issue, and, if they do, as to when, to whom, and with what claims. It is likely that there will be significant litigation and other proceedings, such as interference, re-examination and opposition proceedings, as well as pre- and post-grant review proceedings in various patent offices relating to patent rights in the RNAi field. In addition, third parties may challenge the validity of our patents. For example, a third party has filed an opposition in the European Patent Office, or EPO, against our owned patent EP 2723758, with claims directed to RNAi compositions and methods for silencing ANGPTL3, arguing that the granted claims are invalid. Following an oral hearing in February 2021, the patent was revoked. A notice of appeal of the EPO’s decision was filed in June 2021 and following an oral hearing in November 2023, the appeal was dismissed resulting in the patent remaining revoked. In March 2022, a third party filed an opposition with the EPO against our owned patent EP3105331, which is directed to RNAi compositions and methods for silencing ketohexokinase, seeking to revoke the patent. An oral hearing has not yet been scheduled by the EPO. In addition,
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in February 2023, a third party filed an opposition with the EPO against our owned patent EP 3366775, titled “Modified RNA Agents” seeking to revoke the patent. An oral hearing has been scheduled for November 21 and 22, 2024. Additionally, the validity of two Chinese patents (ZL201380063930.5 and ZL201810143112.0) relating to inclisiran were challenged by a third party in China. The China National Intellectual Property Administration recently issued decisions confirming that patent No. ZL201380063930.5 remained valid as a whole, and patent No. ZL201810143112.0 remained valid based on the amended version of the claims we submitted. We expect that additional oppositions will be filed in the EPO and elsewhere, and other challenges will be raised relating to other patents and patent applications in our portfolio. In many cases, the possibility of appeal exists for either us or our opponents, and it may be years before final, unappealable rulings are made with respect to these patents in certain jurisdictions. The timing and outcome of these and other proceedings is uncertain and may adversely affect our business, prospects, operating results and financial condition if we are not successful in defending the patentability and scope of our pending and issued patent claims. Even if our rights are not directly challenged, disputes could lead to the weakening of our intellectual property rights. Our defense against any attempt by third parties to circumvent or invalidate our intellectual property rights could be costly to us, could require significant time and attention of our management and could have a material adverse effect on our business, prospects, operating results and financial condition and on our ability to successfully compete in the field of RNAi.
There are many issued and pending patents that claim aspects of oligonucleotide chemistry and modifications that we may need for our siRNA products marketed by us or our licensees, our late-stage therapeutic candidates being developed by us or our collaborators, including zilebesiran and fitusiran, as well as our other pipeline products. There are also many issued patents that claim targeting genes or portions of genes that may be relevant for siRNA drugs we wish to develop. In addition, there may be issued and pending patent applications that may be asserted against us in a court proceeding or otherwise based upon the asserting party’s belief that we may need such patents for our siRNA therapeutic candidates or marketed products, or to further develop and commercialize future products, or to continue to develop candidates in our pipeline that are being developed by us or our collaborators. Thus, it is possible that one or more organizations will hold patent rights to which we may need a license, or hold patent rights which could be asserted against us. If those organizations refuse to grant us a license to such patent rights on reasonable terms or at all and/or a court rules that we need such patent rights that have been asserted against us, we may be unable to market our products, including ONPATTRO, AMVUTTRA, GIVLAARI or OXLUMO, or to perform research and development or other activities covered by such patents. For example, during 2017 and 2018, Silence Therapeutics, plc, or Silence, filed claims in several jurisdictions, including the High Court of England and Wales, and named us and our wholly owned subsidiary Alnylam UK Ltd. as co-defendants. Silence alleged various claims, including that ONPATTRO infringed one or more Silence patents. There were also a number of related actions brought by us or Silence in connection with this intellectual property dispute. In December 2018, we entered into a Settlement and License Agreement with Silence, resolving all ongoing claims, administrative proceedings, and regulatory proceedings worldwide between us regarding, among other issues, patent infringement, patent invalidity and breach of contract.
If we become involved in intellectual property litigation or other proceedings related to a determination of rights, we could incur substantial costs and expenses, and in the case of such litigation or proceedings against us, substantial liability for damages or be required to stop our product development and commercialization efforts.
Third parties may sue us for infringing their patent rights. For example, in October 2017, Silence sued us in the UK alleging that ONPATTRO and other investigational RNAi therapeutics we or MDCO were developing infringed one or more Silence patents. In December 2018 we and Silence settled all ongoing litigation between us. A third party may also claim that we have improperly obtained or used its confidential or proprietary information.
Furthermore, third parties may challenge the inventorship of our patents or licensed patents. For example, in March 2011, The University of Utah, or Utah, filed a complaint against us, Max Planck Gesellschaft Zur Foerderung Der Wissenschaften e.V. and Max Planck Innovation, together, Max Planck, Whitehead, MIT and the University of Massachusetts, claiming that a professor of Utah was the sole inventor, or in the alternative, a joint inventor of certain of our in-licensed patents. Utah was seeking correction of inventorship of the Tuschl patents, unspecified damages and other relief. After several years of court proceedings and discovery, the court granted our motions for summary judgment and dismissed Utah’s state law damages claims. During the pendency of this litigation, as well as the Dicerna litigation described below, we incurred significant costs, and in each case, the litigation diverted the attention of our management and other resources that would otherwise have been engaged in other activities.
We may need to resort to litigation to enforce a patent issued or licensed to us or to determine the scope and validity of proprietary rights of others or protect our proprietary information and trade secrets. For example, during the second quarter of 2015, we filed a trade secret misappropriation lawsuit against Dicerna to protect our rights in the RNAi assets we purchased from Merck Sharp & Dohme Corp., or Merck. In April 2018, we and Dicerna settled all claims in the litigation between us. In March 2022, we announced that we separately filed suit in United States District Court for the District of Delaware against Pfizer and Moderna seeking damages for infringement of U.S. Patent No. 11,246,933, or the ’933 patent in the parties’ manufacture and sale of their messenger RNA, or mRNA, COVID-19 vaccines. Pfizer joined BioNTech SE, or BioNTech, to the suit and filed counterclaims. In July 2022, we filed an additional lawsuit in United States District Court for the District of Delaware against each of Pfizer/BioNTech and Moderna seeking damages for infringing U.S. Patent No. 11,382,979, or the
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’979 patent. The court combined the two patents in a single suit for each of Pfizer/BioNTech, or the 2022 Lawsuit, and Moderna with trial dates set for each in November 2024. On May 26, 2023, we filed additional lawsuits against Pfizer and Moderna in Delaware seeking damages for infringing U.S. Patent No. 11,590,229 in the United States District Court for the District of Delaware. In addition to this patent, we added U.S. Patent Nos. 11,633,479 and 11,633,480 in the more recently filed suits against both Pfizer and Moderna and also U.S. Patent No. 11,612,657 against Pfizer only. On August 9, 2023, a Markman hearing was held in the U.S. District Court for the District of Delaware to consider the meaning of three disputed terms as used in the ’933 and ’979 patents, and on August 21, 2023, the court issued an order construing two of the three terms, and deferred a ruling on the third term pending an evidentiary hearing, which was held on January 4, 2024 with the final ruling deferred pending the outcome of an additional hearing, which was held on July 12, 2024. Following the August 21, 2023 order, we and Moderna jointly agreed to final judgment of non-infringement of two of our patents, and that judgment was entered by the court on August 30, 2023, and on September 7, 2023, we appealed the claim construction ruling to the Court of Appeals for the Federal Circuit in the 2022 lawsuit against Moderna. The claim construction ruling initially did not affect one of the patents in the lawsuit filed against Moderna on May 26, 2023, but following a Markman hearing held on August 15, 2024, the court entered a ruling on September 10, 2024, in the same manner as in the earlier case. On October 2, 2024, we and Moderna jointly agreed to final judgment of non-infringement. On October 16, 2024, Moderna filed a motion seeking recovery of fees incurred by them from the time we agreed to a judgment of non-infringement in the first case until the time we agreed to a judgment of non-infringement in the second case, which period runs from approximately September 2023 to October 2024. Our reply is due November 6, 2024. In September 2023, we and Pfizer/BioNTech agreed to consolidate the 2022 Lawsuit and 2023 lawsuits into one case. On January 4, 2024, a hearing was held in the consolidated Pfizer/BioNTech case to construe a final claim, which was subject to an additional evidentiary hearing held on July 12, 2024 with the court issuing its order on August 12, 2024. The trial date for the consolidated Pfizer/BioNTech case is scheduled for July 7, 2025. On July 12, 2024, Acuitas Therapeutics Inc., or Acuitas, filed a declaratory judgment action against us in the U.S. District Court for the District of Delaware, seeking a judgment adding certain Acuitas employees as co-inventors on the patents we have asserted against Pfizer/BioNTech and Moderna in our lawsuits. On September 19, 2024, we filed a motion to dismiss which has not yet been ruled upon. The aforementioned patents relate to our biodegradable cationic lipids that are foundational to the success of the mRNA COVID-19 vaccines.
In protecting our intellectual patent rights through litigation or other means, a third party may claim that we have improperly asserted our rights against them. For example, in August 2017, Dicerna successfully added counterclaims against us in the above-referenced trade secret lawsuit alleging that our lawsuit represented abuse of process and claiming tortious interference with its business. In addition, in August 2017, Dicerna filed a lawsuit against us in the United States District Court of Massachusetts alleging attempted monopolization by us under the Sherman Antitrust Act. As noted above, in April 2018, we and Dicerna settled all claims in the litigation between us.
In addition, in connection with certain license and collaboration agreements, we have agreed to indemnify certain third parties for certain costs incurred in connection with litigation relating to intellectual property rights or the subject matter of the agreements. The cost to us of any litigation or other proceeding relating to such intellectual property rights, even if resolved in our favor, could be substantial, and litigation would divert our management’s efforts. Some of our competitors may be able to sustain the costs of complex patent litigation more effectively than we can because they have substantially greater resources. Uncertainties resulting from the initiation and continuation of any litigation or legal proceeding could delay our research, development and commercialization efforts and limit our ability to continue our operations.
If any parties successfully claim that our creation or use of proprietary technologies infringes upon or otherwise violates their intellectual property rights, we might be forced to pay damages, potentially including treble damages, if we are found to have willfully infringed on such parties’ patent rights. In addition to any damages we might have to pay, a court could issue an injunction requiring us to stop the infringing activity or obtain a license from the claimant. Any license required under any patent may not be made available on commercially reasonable terms, or at all. In addition, such licenses are in many instances non-exclusive and, therefore, our competitors may have access to the same technology that is licensed to us. If we fail to obtain a required license and are unable to design around a patent, we may be unable to effectively market some of our technology and products, which could limit our ability to generate revenues or achieve profitability and possibly prevent us from generating revenue sufficient to sustain our operations. Moreover, we expect that a number of our collaborations will provide that royalties payable to us for licenses to our intellectual property may be offset by amounts paid by our collaborators to third parties who have competing or superior intellectual property positions in the relevant fields, which could result in significant reductions in our revenues from products developed through collaborations.
If we fail to comply with our obligations under any licenses or related agreements, we may be required to pay damages and could lose license or other rights that are necessary for developing, commercializing and protecting our RNAi technology, as well as our approved products and product candidates.
Our current licenses impose, and any future licenses we enter into are likely to impose, various development, commercialization, funding, milestone, royalty, diligence, sublicensing, insurance, patent prosecution and enforcement, and other obligations on us. If we breach any of these obligations, or use the intellectual property licensed to us in an unauthorized manner, we may be required to pay damages and the licensor may have the right to terminate the license or render the license
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non-exclusive, which could result in us being unable to develop, manufacture, market and sell products that are covered by the licensed technology or enable a competitor to gain access to the licensed technology. Moreover, we could incur significant costs and/or disruption to our business and distraction of our management defending against any breach of such licenses alleged by the licensor. For example, in June 2018, Ionis sent us a notice claiming that it was owed payments under our second amended and restated strategic collaboration and license agreement as a result of the January 2018 restructuring of our collaboration agreement with Sanofi and the related Exclusive TTR License and AT3 License Terms. Ionis claimed it was owed technology access fees, or TAFs, based on rights granted and amounts paid to us in connection with the Sanofi restructuring. Ionis later filed a Demand for Arbitration with the Boston office of the American Arbitration Association against us, asserting, among other things, breach of contract. Upon completion of the arbitration process in the second quarter of 2020, in October 2020, a partial award was issued by the arbitration panel that sought additional information from us. The arbitration panel issued its final award in December 2020, which ruled in favor of Ionis’s request for a TAF on certain rights the panel determined we received in the Sanofi restructuring (but rejected the TAF amount sought by Ionis), and in favor of us in denying Ionis’s request for a TAF on a milestone payment received by us in the same restructuring. The panel’s final award also denied Ionis’s request for pre-judgement interest and attorney’s fees. Pursuant to the panel’s final award, we paid $41.2 million to Ionis in January 2021.
Moreover, our licensors may own or control intellectual property that has not been licensed to us and, as a result, we may be subject to claims, regardless of their merit, that we are infringing or otherwise violating the licensor’s rights. In addition, while we cannot currently determine the amount of the royalty obligations we will be required to pay on sales of each of our approved products or future products, if any, the amounts may be significant. The amount of our future royalty obligations will depend on the technology and intellectual property we use in such products. Therefore, even if we successfully develop and commercialize products, we may be unable to achieve or maintain profitability.
Confidentiality agreements with employees and others may not adequately prevent disclosure of trade secrets and other proprietary information.
In order to protect our proprietary technology and processes, we rely in part on confidentiality agreements with our collaborators, employees, consultants, scientific advisors, CMOs, outside scientific collaborators and sponsored researchers, and other advisors. These agreements may not effectively prevent disclosure of confidential information and may not provide an adequate remedy in the event of unauthorized disclosure of confidential information. In addition, other third parties may independently discover trade secrets and proprietary information, and in such cases we could not assert any trade secret rights against such party. Costly and time-consuming litigation could be necessary to enforce and determine the scope of our proprietary rights, and failure to obtain or maintain trade secret protection could adversely affect our business, prospects, operating results and financial condition.
Risks Related to Competition
The pharmaceutical market is intensely competitive. If we or our collaborators are unable to compete effectively with existing drugs, new treatment methods and new technologies, we or our collaborators may be unable to commercialize successfully any drugs that we or our collaborators develop.
The pharmaceutical market is intensely competitive and rapidly changing. Many large pharmaceutical and biotechnology companies, academic institutions, governmental agencies and other public and private research organizations are pursuing the development of novel drugs for the same diseases that we are targeting or expect to target. Many of our competitors have:
substantially greater financial, technical and human resources than we have;
more extensive experience in pre-clinical testing, conducting clinical trials, obtaining regulatory approvals, and in manufacturing, marketing and selling drug products;
product candidates that are based on previously tested or accepted technologies;
multiple products that have been approved or are in late stages of development; and
collaborative arrangements in our target markets with leading companies and research institutions.
We will face intense competition from drugs that have already been approved and accepted by the medical community for the treatment of the conditions for which we may develop drugs. In addition, there are a number of drugs currently under development and that may become commercially available in the future, for the treatment of conditions for which we may try to develop drugs. These drugs may be more effective, safer, less expensive, have more convenient administration or be marketed and sold more effectively, than any products we develop and commercialize.
For example, assuming regulatory approval, vutrisiran, our RNAi therapeutic in development for treatment of ATTR amyloidosis with cardiomyopathy, would compete with VYNDAQEL/VYNDAMAX (tafamidis), marketed by Pfizer, which is currently approved to treat this disease. In addition, BridgeBio announced positive results from its Phase 3 clinical trial of acoramidis, a TTR stabilizer, in ATTR amyloidosis with cardiomyopathy in July 2023, and announced in February 2024 that the FDA accepted its NDA for filing with a PDUFA action date of November 29, 2024. BridgeBio also announced that the
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EMA accepted its marketing authorization application with a decision expected in 2025, and that it anticipates additional global regulatory submissions. We are also aware of other product candidates in clinical development for the treatment of ATTR amyloidosis with cardiomyopathy, including WAINUA (eplontersen), a drug being developed by Ionis and AstraZeneca plc, or AstraZeneca, and is in Phase 3 clinical development; NTLA-2001, which is being developed by Intellia Therapeutics, Inc. and Regeneron and is in Phase 3 clinical development; NNC-6019, which is being developed by Novo Nordisk and is in Phase 2 clinical development; and NI006, which is being developed by Neurimmune AG and AstraZeneca plc and is in Phase 3 clinical development. We expect to face competition from any of these and potentially other additional new drugs that enter the market to treat patients with ATTR amyloidosis with cardiomyopathy.
ONPATTRO and AMVUTTRA are approved in certain jurisdictions for the treatment of certain patients with hATTR amyloidosis with polyneuropathy. We are aware of other approved products used to treat this disease, including WAINUA (eplontersen), a drug developed by Ionis in partnership with AstraZeneca, VYNDAQEL/VYNDAMAX (tafamidis), and TEGSEDI (inotersen), which is developed and marketed by Ionis. There are also product candidates in various stages of clinical development for the treatment of hATTR amyloidosis patients with polyneuropathy. While we believe that ONPATTRO and AMVUTTRA have and will continue to have a competitive product profile for the treatment of patients with hATTR amyloidosis with polyneuropathy, it is possible that ONPATTRO and/or AMVUTTRA may not compete favorably with these products and product candidates, or others, and, as a result, may not achieve commercial success.
If we or our collaborators continue to successfully develop product candidates, and obtain approval for them, we and our collaborators will face competition based on many different factors, including:
the safety and effectiveness of our or our collaborators’ products relative to alternative therapies, if any;
the ease with which our or our collaborators’ products can be administered and the extent to which patients accept relatively new routes of administration;
the timing and scope of regulatory approvals for these products;
the availability and cost of manufacturing, marketing and sales capabilities;
the price of our or our collaborators’ products relative to alternative approved therapies;
reimbursement coverage; and
patent position.
We are aware of product candidates in various stages of clinical development for the treatment of PH1 which would compete with OXLUMO, our RNAi therapeutic approved in the U.S. and EU for the treatment of this disease, including Novo Nordisk’s product RIVFLOZA (nedosiran), which was approved for the treatment of PH1 in September 2023 and launched in the U.S. in early 2024. RIVFLOZA is a once-monthly subcutaneous RNAi therapy that was developed by Dicerna. In April 2020, we and Dicerna granted each other a non-exclusive cross-license to our respective intellectual property related to lumasiran and Dicerna’s nedosiran. In addition, several companies have investigational drugs in clinical development for the treatment of PH1, including BridgeBio, Chinook Therapeutics, Inc., and BioMarin Pharmaceutical, Inc.
Our competitors may develop or commercialize products with significant advantages over any products we or our collaborators develop based on any of the factors listed above or on other factors. In addition, our competitors may develop collaborations with or receive funding from larger pharmaceutical or biotechnology companies, providing them with an advantage over us and our collaborators. Our competitors may therefore be more successful in commercializing their products than we or our collaborators are, which could adversely affect our competitive position and business, prospects, operating results and financial condition. Competitive products may make any products we or our collaborators develop obsolete or noncompetitive before we can recover the expenses of developing and commercializing our product candidates. Such competitors could also recruit our employees, which could negatively impact our level of expertise and our ability to execute on our business plan. Furthermore, we and our collaborators also face competition from existing and new treatment methods that reduce or eliminate the need for drugs, such as the use of advanced medical devices. The development of new medical devices or other treatment methods for the diseases we and our collaborators are targeting could make our or our collaborators’ product candidates noncompetitive, obsolete or uneconomical.
We and our collaborators face competition from other companies that are working to develop novel drugs and technology platforms using technology similar to ours, as well as from companies utilizing emerging technologies. If these companies develop drugs more rapidly than we or our collaborators do or their technologies, including delivery technologies, are more effective, our and our collaborators’ ability to successfully commercialize our products may be adversely affected.
In addition to the competition we face from competing drugs in general, we and our collaborators also face competition from other companies working to develop novel drugs using technology that competes more directly with our own. We are aware of several other companies that are working to develop RNAi therapeutic products. Some of these companies are seeking, as we are, to develop chemically synthesized siRNAs as drugs. Others are following a gene therapy approach, with the goal of treating patients with synthetic, exogenously-introduced genes designed to produce siRNA-like molecules within cells.
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Companies working on chemically synthesized siRNAs include, but are not limited to, Arrowhead and its collaborators, Takeda Pharmaceutical Company Ltd., Janssen Pharmaceutics, Inc., GlaxoSmithKline plc, and Amgen Inc.; Quark Pharmaceuticals, Inc.; Roche; Silence Therapeutics plc and its collaborators, AstraZeneca, Jiangsu Hansoh Pharmaceuticals Group Co., Ltd., and Mallinckrodt plc; Arbutus; Sylentis; and Novo Nordisk and its collaborators, Boehringer Ingelheim and Eli Lilly and Company. In addition, we granted licenses or options for licenses to Ionis, Benitec Biopharma Ltd., Arrowhead, Arbutus, Quark, Sylentis and other companies under which these companies may independently develop RNAi therapeutics against a limited number of targets. Any one of these companies may develop its RNAi technology more rapidly and more effectively than we do. In addition, as a result of agreements that we have entered into, Takeda has obtained a non-exclusive license, and Arrowhead, as the assignee of Novartis, has obtained specific exclusive licenses for 30 gene targets, that include access to certain aspects of our technology.
We and our collaborators also compete with companies working to develop antisense-based drugs. Similar to RNAi therapeutics, antisense drugs target mRNAs in order to suppress the activity of specific genes. Akcea Therapeutics, Inc., a wholly owned subsidiary of Ionis, has received marketing approval for an antisense drug, inotersen for the treatment of adult hATTR amyloidosis patients with stage 1 or stage 2 polyneuropathy. Several antisense drugs developed by Ionis have been approved and are currently marketed, including WAINUA (eplontersen), and Ionis has multiple antisense product candidates in clinical trials. Ionis is also developing antisense drugs using ligand-conjugated GalNAc technology licensed from us, and these drugs have been shown to have increased potency at lower doses in clinical and pre-clinical studies, compared with antisense drugs that do not use such licensed GalNAc technology. The development of antisense drugs and antisense technology may become the preferred technology for drugs that target mRNAs to silence specific genes.
In addition to competition with respect to RNAi and with respect to specific products, we face substantial competition to discover and develop safe and effective means to deliver siRNAs to the relevant cell and tissue types. If our competitors develop safe and effective means to deliver siRNAs to the relevant cell and tissue types, our ability to successfully commercialize a competitive product would be adversely affected. In addition, third parties are expending substantial resources to discover and develop a safe and effective means of delivering siRNAs into the relevant cell and tissue types, including both private companies and academic laboratories. Some of our competitors have substantially greater resources than we do, and if our competitors negotiate exclusive access to delivery solutions developed by third parties, we may be unable to successfully commercialize our product candidates.
Risks Related to Our Common Stock
Our stock price has been and may in the future be volatile, and an investment in our common stock could suffer a decline in value.
Our stock price has been and may in the future be volatile. The stock market in general and the market for biotechnology companies in particular have experienced extreme price and volume volatility that has often been unrelated to the operating performance of particular companies. The market price of our common stock in the future could be significantly and adversely affected by many factors, including:
包含在我們季度收益發布中的信息,包括關於我們或我們合作伙伴的商業化產品或候選產品的更新,我們的淨產品和合作收入以及已完成期間的營業費用,以及有關未來時期的財務指導。
現有或新的競爭產品或技術的成功;
關於我們或我們合作伙伴的產品或候選產品的監管行動;
我們或競爭對手宣佈重大收購、合作、合資、合作或資本承諾;
我們或合作伙伴的其他產品候選品的臨床試驗時間和結果;
我們開展或終止合作開發計劃;
我方或合作方任何開發計劃的失敗或中止;
我們競爭對手產品候選品的臨床試驗結果;
美國和其他國家的監管或法律發展;其他。
涉及專利申請、已發專利或其他專有權利的發展或爭議;
招募或離職關鍵人員;
與任何我們的產品候選者或臨床開發項目相關的費用水平;
我們或我們的合作伙伴努力開發更多產品候選者或產品的成果;
財務業績或發展時間表的實際或預期變化;
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宣佈或預期額外融資努力;
我們公司、我們的內部人員或其他股東出售我們的普通股;
我們的財務結果或那些被認爲與我們相似的公司的變化;
證券分析師調整對我們的估價或推薦
醫療支付體系結構的變化;
藥品和生物技術領域的市場情況;
一般的經濟、行業板塊和市場狀況;以及
本「風險因素」一節中描述的其他因素。
過去,證券訴訟往往是在市場價格下跌後針對公司提起的。這種風險對於生物製藥公司尤爲重要,近年來這些公司股價波動顯著。例如,2019年9月,我們及部分現任和前任董事和高管,以及我們2017年11月股票發行的承銷商,被提起了一起聲稱違反聯邦證券法的集體訴訟。雖然此事已最終和解,但我們可能將來會成爲此類訴訟的目標。針對我們的證券訴訟可能導致巨額成本,並分散我們管理層的注意力和資源,可能對我們的業務、前景、運營結果和財務狀況造成嚴重損害。我們持有責任保險;然而,如果與訴訟相關的任何成本或費用超過我們的保險範圍,我們可能被迫直接承擔其中一部分或全部的成本和費用,這可能會是巨大的。此外,我們有義務爲第三方提供賠償,包括我們的高管和董事以及我們證券發行的承銷商,與某些訴訟有關,那些義務可能不被保險覆蓋。
公司普通股的大量股份銷售,包括我們、我們的高管或董事以及我們的重要股東,在公開市場上可能導致我們的普通股價格下跌。
我們的少數股東擁有大量普通股。截至2024年9月30日,我們八大股東持有超過50%的流通普通股。如果我們、我們的高管或董事,或我們的重要股東在公開市場大量出售我們的普通股,或者有這種銷售可能的印象,那麼我們的普通股市場價格可能會受到不利影響。重要股東出售普通股可能會使我們更難以在我們認爲合適的時間和價格出售股權或股權相關證券以籌集資金。
我們章程中和特拉華州法律下的反收購條款可能使得對我們的收購更加困難,也可能阻止股東嘗試替換或罷免我們現有管理層或董事會成員。
我們公司章程和公司規則中的條款可能會延遲或阻止我們的收購,或者延遲或阻止當前管理成員或董事會成員的變更。其中包括以下幾點:
成立一個分類董事會,使我們董事會的所有成員不是同時選舉產生的;
設立禁令,禁止股東通過書面同意進行行動;
授權我們的董事會在無需股東批准的情況下發行優先股,從而可以使用「毒丸」來稀釋潛在敵意收購者的股權,有效防止未經我們董事會批准的收購。
只有董事會通過決議才能更改授權的董事人數。
限制可以召開股東特別會議的人;
需要至少得到所有股東有權投票的75%的股份持有人批准,才能修訂或廢除我們公司章程或章程的某些條款。
限制股東可刪除我們董事會董事的方式;和
設立提前通知要求,以便提名董事會候選人,並提出股東大會可處理事項。
此外,由於我們是在特拉華州註冊成立的,受特拉華州公司法第203條的規定約束,該法規禁止持有我們超過15%的表決股票的人在收購我們超過15%的表決股票之日起的三年內與我們合併或結合,除非經規定方式獲得批准。即使有些股東認爲擬議的合併或收購可能有利,這些條款也將適用。
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我們預期,我們和合作夥伴的臨床開發活動以及競爭對手的臨床開發活動的結果將繼續週期性發佈,可能導致我們普通股價格出現顯著波動。
有關我方及合作伙伴的產品和產品候選品、競爭產品或潛在競爭產品的任何新資訊,可能會對投資者對我們未來前景的看法產生重大影響。我們自己、我們的合作伙伴和我們的競爭對手定期發佈有關藥物開發計劃的更新,通常通過新聞發佈、電話會議以及在醫學會議上的演講。這些定期更新通常包括我們或我們的競爭對手在臨床試驗中獲得的中期或最終結果,以及關於我們或我們競爭對手對監管備案和提交以及未來臨床開發計劃的期望的信息,涉及我們產品或產品候選品、競爭產品或潛在競爭產品。我們發佈有關藥物開發計劃的信息的時間往往超出我們的控制,並受到我們的臨床試驗數據接收時間以及製藥公司普遍傾向在醫學會議期間披露臨床數據的影響。此外,我們或競爭對手的臨床試驗披露的信息可能基於中期而非最終數據,可能存在解釋困難,甚至無法準確預測最終結果。這類信息的披露可能導致我方普通股價格波動。例如,2021年底BridgeBio對acoramidis用於治療帶有心肌病變的ATTR澱粉樣蛋白病的3期臨床試驗A部分結果進行公開披露後,我們的股價受到了負面影響。
與我們的可轉換債券相關的風險
我們可能沒有足夠的現金流來償還債務。
截至2024年9月30日,我們已發行並尚未償付的債券總額爲10.4億美元。債券的利率固定在每年1.00%,並應在每年5月15日和9月15日後半年支付一次,自2023年3月15日起開始。我們償還本息、償付債務利息、或重新融資(包括債券),或在與任何債券轉換相關的現金支付方面支付的能力取決於我們未來的業績,受經濟、財務、競爭和其他我們無法控制的因素的影響。我們的業務未來可能無法產生足夠的經營現金流量來償還債務並進行必要的資本支出。如果我們無法產生這樣的現金流,我們可能需要採取一項或多項替代措施,例如出售資產、重組債務、或以可能十分苛刻或高度稀釋的條件融資或獲得額外債務融資或股本資金。我們未來償還債務的能力將取決於資本市場和我們當時的財務狀況。我們可能無法從事任何這些活動,或者以理想的條件從事這些活動,這可能導致我們違約債務責任。
此外,我們的債務加上其他財務義務和合約承諾可能會產生其他重要後果。例如,它可能會:
使我們更容易受到美國和全球經濟、行業和競爭條件以及政府監管不利變化的影響。
限制了我們對業務和行業板塊變化做出規劃或反應的靈活性;
與債務較少的競爭對手相比,使我們處於不利位置;
限制我們借入額外資金用於收購,營運資金和其他一般公司用途;和
使得收購我們公司變得不那麼具吸引力或更加困難。
這些因素中的任何一個都可能損害我們的業務、前景、運營結果和財務狀況。此外,如果我們負擔額外的債務,與我們業務相關的風險以及我們償還或償還債務的能力的風險將增加。
我們可能沒有能力籌集必要的資金來以現金形式償付票據或在基本變更後以現金回購票據。
持有票據的持有人有權要求我們在出現基本變更(定義在管理票據的契約中)時,按等於待回購票據本金金額的100%加上應計及未付利息(如有)的回購價格回購他們的票據。在票據轉換過程中,除非我們選擇僅提供我們的普通股份來結算此類轉換(而非支付現金以替代提供任何零股),否則我們將需要支付現金以換取正在轉換的票據。在我們需要回購被交出的票據或正在轉換的票據時,我們可能沒有足夠的現金或無法在該時期獲得融資。此外,根據法律、監管機構或管理我們未來債務的協議,我們回購票據或支付現金以換取票據的能力可能受到限制。如果我們未能在規定的時期回購根據此類契約規定應該回購的票據,或未能按照此類契約要求支付未來轉換的票據的任何現金,都將構成違約。根據管理票據或基本變更的契約的違約也可能導致違約下我們未來債務管理協議。如果
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倘若有關債務被加速清償,經適用通知或寬限期後,我們可能無法獲得足夠的所有基金類型來償還債務、回購票據或支付轉換現金。
如果觸發,Notes的條件性轉換功能可能會對我們的流動性產生不利影響。
如果發生票據的條件轉換功能,票據持有人將有權在特定時期任選時間轉換票據。如果一個或多個持有人選擇轉換他們的票據,除非我們選擇通過交付我們的普通股(而不是支付現金來應付任何零頭股份)滿足我們的轉換義務,否則我們將需要通過支付現金解決部分或全部轉換義務,這可能對我們的流動性造成不利影響。此外,即使持有人不選擇轉換他們的票據,根據適用的會計準則,我們可能會被要求將所有或部分尚未償還的票據本金重新分類爲流動負債,而不是長期負債,這將導致我們的淨營運資本大幅減少。
與票據相關的交易可能會影響我們普通股的價值。
如果我們在履行轉換義務時通過交付我們的普通股來履行轉換義務,可能會導致現有股東的所有權利受到稀釋。在某些情況下,這些債券未來可能會按其持有人的選擇轉換。如果債券持有人選擇轉換其債券,我們可能會通過向他們交付大量我們的普通股來結算我們的轉換義務,這將導致對現有股東的稀釋。
另外,關於發行票據,我們與某些金融機構(或期權對手方)簽訂了帶頂限的認購權益交易。這些帶頂限的認購權益交易通常預計可以在任何轉換或清償票據時減少對我們普通股的潛在稀釋,並/或抵消我們根據轉換票據超過本金金額而需要支付的任何現金付款,該減少和/或抵消受到一定上限的約束。
關於建立頭寸限制型看漲期權的初始對沖,期權交易對手或其各自的關聯方同時或在發行票據定價後不久,與我們的普通股相關,進行了各種衍生交易和/或購買了我們的普通股。
不時地,期權交易對手或其各自的關聯方可能會通過進行或解除各種與我們普通股有關的衍生交易,或在票據到期之前在二級市場交易中購買或出售我們的普通股或其他證券,來調整其對沖頭寸(在票據轉換、我們在基本變更贖回日期上贖回票據、贖回日期上、或我們終止上限認購相關部分期權時,可能會在此後進行此類操作)。這一活動可能導致我們的普通股市場價格下跌和/或波動增加。
我們不就上述交易可能對票據或普通股價格產生的任何潛在影響的方向或幅度作出任何陳述或預測。此外,我們不作出期權交易對手將進行這些交易的任何陳述,或者一旦開始這些交易將不會在未經通知的情況下終止。
我們在關於已設上限認購期權方面面臨交易對手風險。
期權交易對手是金融機構,可能面臨的風險是其中任何一個或所有的交易對手可能會在封頂認購期權中違約。我們對期權交易對手的信用風險將不會被任何抵押物擔保。過去的全球經濟狀況導致許多金融機構實際或被認爲陷入失敗或財務困境。如果期權交易對手成爲破產程序的對象,我們將成爲這些程序中的無抵押債權人,債權金額等於此時我們在與該期權交易對手之間的封頂認購期權下的敞口。我們的敞口將取決於許多因素,但一般情況下,我們的敞口增加將與我們的普通股市場價格和波動率增加相關。此外,如果期權交易對手違約,我們可能面臨不利的稅務後果,並有可能蒙受比我們目前預期的更大程度的普通股攤薄。我們無法保證期權交易對手的財務穩定性或可行性。
可轉換債務證券的會計處理方法,例如票據這類可以以現金結算的債務證券,可能對我們報告的財務結果產生重大影響。
在我們的簡明綜合資產負債表中反映票據的會計方法,爲票據計提利息費用並在我們報告的攤薄每股收益中反映我們普通股的基礎股票,可能會對我們的報告收入和財務狀況產生不利影響。
2020年8月,FASB發佈了一項會計準則更新,我們稱之爲ASU 2020-06,簡化了適用於可轉換票據的某些會計準則。ASU 2020-06自2022年1月1日起生效。
根據ASU 2020-06,註釋作爲負債反映在我們的簡明綜合資產負債表上,初始賬面價值等於註釋的本金淨髮行成本。發行成本被視爲
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會計目的的負債折扣,正在攤銷爲債券期間的利息支出。由於這種攤銷,我們預計會計目的上對於債券的利息支出將大於我們實際支付的現金利息支出,這將導致報告的淨利潤較低或報告的淨虧損較高,具體情況視情況而定。
此外,按照ASU 2020-06的規定,我們使用"如合併"方法在稀釋每股收益中反映普通股票下對應的普通股。按照此方法,一般來說,在報告期的開始時假設所有票據僅轉換爲普通股,除非結果將導致抵消稀釋。若未來盈利,如合併方法的應用可能會降低我們報告的稀釋每股收益,而會計準則可能會在未來發生變化,可能會對我們的稀釋每股收益產生不利影響。
此外,如果符合債券可轉換條件的任何一項,則根據適用的會計準則,我們可能需要將債券的負債賬面價值重新分類爲流動負債,而不是長期負債。即使沒有持有人實際轉換其債券,也可能要求進行這種重新分類,這可能會對我們報告的營運資金產生重大影響。
第5項其他信息
採納10b5-1計劃 交易計劃 由我們的高管和董事
在2024年9月30日結束的財政季度中,我們的某些高管(根據《證券交易法》第16a-1(f)條規定)和董事們簽訂了旨在滿足《證券交易法》第10b5-1(c)條規定條件的證券購買或出售合同、指示或書面計劃,以便對根據非公開重要信息進行證券交易的責任提出肯定性軍工股抗辯。我們將這些合同、指示和書面計劃稱爲「第10b5-1交易計劃」,每一個稱爲「第10b5-1交易計劃」。我們將這些第10b5-1交易計劃的重要條款描述如下。
David E.I.Pyott, 董事
2024年6月4日,Realty Income公司(以下簡稱「公司」)發佈了一份新聞稿,公佈了截至2024年12月31日更新的收益和投資成交量預測。新聞稿的副本作爲Exhibit 99.1附在此,作爲本報告的一部分。此報告的Exhibit 99.1作爲第7.01項目,根據8-K表格的規定提供,不視爲1934年證券交易法第18條的「報告文件」,無論此後公司做出的任何註冊文件,也不管任何這類文件的一般包含語言,都不作爲參考依據。2024年9月5日大衛·E·I·帕約特,是我們董事會成員之一, 簽訂了一項第10b5-1條例交易計劃 計劃規定帕約特先生,通過經紀人,可賣出最多 7,440 股普通股,這些股份是作爲董事報酬授予帕約特先生的期權行使後收到的,根據拆股並股、股份送轉、其他類似調整我們普通股的情況進行調整。在2025年1月1日至2025年12月17日期間,只有當我們普通股的市場價格高於指定價格時,計劃才能進行股份的銷售。該計劃預定於 2025年12月17日終止,但在出售計劃中規定的所有股份、帕約特先生或經紀人終止,或根據計劃中提供的其他條件之前,可能會提前終止。
Pushkal P. Garg, 首席醫療官
2024年6月4日,Realty Income公司(以下簡稱「公司」)發佈了一份新聞稿,公佈了截至2024年12月31日更新的收益和投資成交量預測。新聞稿的副本作爲Exhibit 99.1附在此,作爲本報告的一部分。此報告的Exhibit 99.1作爲第7.01項目,根據8-K表格的規定提供,不視爲1934年證券交易法第18條的「報告文件」,無論此後公司做出的任何註冊文件,也不管任何這類文件的一般包含語言,都不作爲參考依據。2024年9月11日,我們的首席醫療官Pushkal P. Garg, 已經制定了一項規則10b5-1交易計劃 ,規定了通過經紀人代表Garg博士進行交易,最多可以賣出 94,925 股我們普通股票的總數,這些股票是作爲激勵補償授予給Garg博士的獎勵的結算所獲得的,根據普通股的拆股並股、股票特別股和其他類似變更進行調整。計劃規定,此計劃僅可在2024年12月12日至2025年12月18日期間進行股票出售。計劃安排在 2025年12月18日日終止,但可以提前終止,條件是根據計劃的全部條款出售了計劃所涉及的全部股份,由Garg博士或經紀人終止,或者按計劃中另行規定。
伊馮·L·格林斯特里特,MBChb,MBA, 首席執行官和董事
2024年6月4日,Realty Income公司(以下簡稱「公司」)發佈了一份新聞稿,公佈了截至2024年12月31日更新的收益和投資成交量預測。新聞稿的副本作爲Exhibit 99.1附在此,作爲本報告的一部分。此報告的Exhibit 99.1作爲第7.01項目,根據8-K表格的規定提供,不視爲1934年證券交易法第18條的「報告文件」,無論此後公司做出的任何註冊文件,也不管任何這類文件的一般包含語言,都不作爲參考依據。2024年9月12日, Yvonne L. Greenstreet, MBChb, MBA, 我們的首席執行官, 簽訂了一項規則10b5-1交易計劃 該計劃規定格林斯崔特博士通過經紀人最多可賣出合計 50,937 股我們普通股中獎勵賦予格林斯崔特博士作爲股權激勵薪酬的解鎖後可獲得的股票份額,根據拆股並股、股票送轉、股票分紅及我們普通股的其他類似變化進行調整。計劃規定,僅當我們的普通股市場價格從2024年12月16日至2025年6月6日高於特定價格時,才可根據該計劃出售股票。該計劃計劃在 2025年6月6日到期,但若提前售出計劃下所有股份、由格林斯崔特博士或經紀人終止,或計劃中另有規定,則可能提前終止。
Tolga Tanguler, 首席商務官
2024年6月4日,Realty Income公司(以下簡稱「公司」)發佈了一份新聞稿,公佈了截至2024年12月31日更新的收益和投資成交量預測。新聞稿的副本作爲Exhibit 99.1附在此,作爲本報告的一部分。此報告的Exhibit 99.1作爲第7.01項目,根據8-K表格的規定提供,不視爲1934年證券交易法第18條的「報告文件」,無論此後公司做出的任何註冊文件,也不管任何這類文件的一般包含語言,都不作爲參考依據。2024年9月12日,Tolga Tanguler,我們的首席商業官, 簽訂了規則10b5-1交易計劃 允許Tanguler先生,通過經紀人,最多賣出 4,070 股份,這些股份是作爲股權激勵補償向Tanguler先生授予的獎勵的結算後收到的,根據拆股並股、股票組合、送轉和其他類似變更進行調整。計劃規定,計劃僅在2024年12月13日至2025年5月10日期間,如果我們的普通股的市場價格高於指定價格,方可出售計劃中的股份。計劃定於 2025年5月10日結束,若所有計劃中的股份已出售,Tanguler先生或經紀人提前終止,或計劃中另有規定。
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展品6. 陳列品
10.1#†
31.1#
31.2#
32.1#+
32.2#+
101.SCH行內XBRL分類擴展模式文檔
101.CALInline XBRL稅務分類擴展計算鏈接庫文檔
101.LAB行內XBRL分類擴展標籤鏈接庫文檔
101.PRE行內XBRL分類擴展演示鏈接庫文檔
101.DEF行內XBRL分類擴展定義鏈接庫文檔
104交互數據文件封面(格式爲內聯XBRL,其中包含在展品101(*)中適用的分類擴展信息)

#隨此提交。
根據證券交易委員會的規定,本展覽的部分內容(由星號標示)已被省略,因爲這些信息(i)不是重要信息,且(ii)如果公開披露可能會對註冊人造成競爭性損害。
+根據1934年修訂版的《證券交易法》第18條的規定,本證書不會被視爲「已申報」,也不會受到該條款的責任限制。該證書不會被視爲被引用並納入任何根據1933年修訂版的《證券法》或《證券交易法》的文件,除非明確被引用並納入到該文件中。

76

目錄
簽名
根據1934年證券交易法的要求,本公司已授權其代表在此簽署本報告。
ALNYLAm製藥公司。
日期:2024年10月31日Yvonne L. Greenstreet,MBChb,MBA
Yvonne L. Greenstreet,MBChb,MBA
首席執行官
簽名:/s/ Ian Lee
日期:2024年10月31日Jeffrey V. Poulton
Jeffrey V. Poulton
執行副總裁,首席財務官
(信安金融及會計主管)

77