Cemdisiran

丨猎药人俱乐部研究团队整理 小核酸药物经多年发展，重磅产品不断涌现。渤健与Ionis开发的Nusinersen是目前销售额最高的小核酸药物，2019-2020年全球销售额均超过20亿美元；诺华与Alnylam开发的 leqvio(Inclisiran) 是一款长效降脂药，一年仅需注射两次，开启了小核酸药物应用于常见慢性病的新篇章。根据诺华最新财报显示，leqvioQ3单季销售大卖1.98亿美金（同比120%），全年已卖超5.31亿美金（同比129%）。 不过leqvio仍在不断扩张适用边界，除了公司已计划提交用于降低低或中等ASCVD风险患者的LDL-C水平的上市申请，诺华也开展了VictORION系列研究，其中包含业内唯一一项在高危一级预防人群中探索非他汀类降脂疗法效果的研究。 在国内，Leqvio于2023年8月获国家药监局批准上市，作为饮食的辅助疗法，用于成人原发性高胆固醇血症（杂合子型家族性和非家族性）或混合型血脂异常患者的治疗。诺华Q1季报显示，国内每天新增患者超过250名，按此规模估算，Leqvio在中国的销售额接近30亿元。而随着近日国谈结束，医保落地后，将会有更多患者使用并收益。 leqvio已然成为了小核酸赛道的“璀璨新星”，而随着小核酸技术的逐渐成熟和应用的不断扩展，未来我们也期待该赛道迎来更多的“重磅药物”。本文根据国内外各调研机构的数据，统计了14款值得关注的小核酸药物，其中包括未来有望成为销售额＞10亿美元“重磅药物”的7款药物，仅供参考。 具有＞10亿美元“重磅”潜力小核酸药物 01 首次纳入医保，持续拓宽边界，leqvio“天花板”有多高？ 2024年10月31日，根据最新一次国家医保谈判结果，首次参与国家医保谈判的诺华制药研发的「英克司兰钠注射液」（Inclisiran，商品名：乐可为 Leqvio）本次定价9988元针。在谈判前，乐可为的全球市场定价为每针3250美元（约合人民币23769元），一年两针共计6500美元（约合人民币47538元），降幅达58%。 作为全球首个且唯一siRNA超长效降脂药物（慢病用药），该药注射液的给药方式是单次皮下注射，首次给药后，患者需要在3个月和每6个月时分别进行再次给药。因此，一般患者每年可能需要接受两到三针的治疗，每年的费用大约在2万到3万元人民币之间。 纳入医保显然能够助推PCSK9放量。以最早上市的安进的依洛尤单抗为例，它于2015年获批，于2021年纳入医保目录，直接从每针1300元，年费用3万多元，降到了每针300元，年费用7000元左右，降幅达77%。 依洛尤单抗虽早在2021年就突破10亿美元门槛，成为重磅级产品，但随着放量速度持续猛涨，到2023年营收已飙升至16.35亿美元。从国内市场看，据中康开思系统显示，依洛尤单抗在2023年等级医院的销售额达11.41亿元，同比上涨134.7%。 依洛尤单抗全国等级医院销售额（来源：中康开思系统） 从市场格局来看，Leqvio虽然也承受着来自依洛尤单抗、托莱西单抗等PCSK9单抗的竞争压力，但增长势头良好，诺华仍然在继续扩展Leqvio的应用边界。 今年8月28日，诺华宣布III期V-MONO研究取得了积极结果。该研究旨在评估每年两次给药的Leqvio（inclisiran，英克司兰）对比安慰剂、ezetimibe（依折麦布）治疗低、中危且未接受过降脂治疗的动脉粥样硬化性心血管疾病（ASCVD）患者的疗效和安全性。结果显示，该研究达到了主要终点，Leqvio降低了患者的低密度脂蛋白胆固醇（LDL-C）水平。公司已计划提交该药物用于降低低或中等ASCVD风险患者的LDL-C水平的上市申请。 此外，为探索Leqvio对心血管结局的潜在益处，从而扩大该药物的适用人群，诺华开展了VictORION系列研究，例如： VICTORION-1 PREVENT（V1P）研究（n=14000）：评估Leqvio对比安慰剂在高危一级预防患者中预防主要心血管不良事件的有效性和安全性； VICTORION-2 PREVENT（V2P）研究（n=17006）：评估Leqvio对比安慰剂在高危二级预防患者中预防主要心血管不良事件的有效性和安全性； VICTORION-INCEPTION研究（n=384）：评估Leqvio联合常规治疗（Usual Care）对比常规治疗降低近期出现急性冠状动脉综合征（ACS）患者的LDL-C水平的有效性和安全性； VICTORION-INCLUSION研究（n=1440）：评估Leqvio联合常规治疗对比常规治疗降低高危或已确诊ASCVD患者的LDL-C水平的有效性和安全性。 ORION-4研究（n=16124）：评估Leqvio对比安慰剂改善ASCVD患者的临床结局的有效性和安全性。 其中，V1P研究是唯一一项在高危一级预防人群中探索非他汀类降脂疗法效果的研究。ORION-4和V2P研究的结果分别有望在2026年和2027年获得数据。 根据市场调研机构GlobalData预测，Leqvio的销售额将稳步增长，到 2030年该药物的全球销售额将达到34亿美元。 02 14款值得关注的小核酸药物 1）预计年底获批：2款 Ionis：Olezarsen 作用机制:ApoC3抑制剂 适应症:家族性乳糜微粒血症综合征（FCS）2030年销售额预测：3.99亿美元（根据cortellis） Olezarsen是一种ASO疗法，能够抑制机体产生ApoC3。ApoC3是一种在肝脏中产生、调节血液中甘油三酯（TG）代谢的蛋白。Balance临床3期试验结果显示，FCS患者每四周接受一次80 mg olezarsen皮下注射治疗，患者的TG水平持续显著降低（经安慰剂调整），治疗6个月降幅为44%；治疗第6个月到第12个月期间降低59%；经安慰剂调整后的apoC3降幅在接受治疗6个月时为74%，在12个月时为81%。美国FDA已接受olezarsen用于治疗FCS成人患者的新药申请（NDA）并授予优先审评资格，预计在2024年12月19日前完成审评。Ionis还计划在今年在欧盟和加拿大递交监管申请。根据cortellis预测，Olezarsen 2030年销售额有望达到3.99亿美元。 赛诺菲/Alnylam：Fitusiran 作用机制:抗凝血酶III抑制剂 适应症:血友病A与血友病B2030年销售额预测：2.98亿美元（根据cortellis） Fitusiran是一款小干扰RNA（siRNA）疗法，旨在作为体内产生/未产生凝血因子抑制物的血友病A或血友病B患者的预防性治疗。Fitusiran可降低抗凝血酶水平，从而促进凝血酶生成，重新平衡止血功能并预防出血。在两项3期临床研究中，与对照组相比，每月一次皮下注射fitusiran预防治疗组患者的年化出血率降低了90%。Fitusiran注射液的上市申请已于2024年5月获得中国国家药监局（NMPA）受理，并于6月获得美国FDA受理。根据cortellis预测，Fitusiran 2030年销售额有望达到2.98亿美元。 2）销售预测＞10亿美元的潜力重磅药物：7款Arrowhead：ARO-ANG3 作用机制：ANGPTL3抑制剂 适应症：血脂异常、家族性高胆固醇血症（FH）、高甘油三酯血症（HTG） 销售峰值预测：45亿美元（根据Zacks Investment Research） ARO-ANG3是公司开发的一款靶向血管生成素样蛋白3（ANGPTL3）的RNAi疗法，被开发用于治疗血脂异常、家族性高胆固醇血症（FH）、高甘油三酯血症（HTG）。2024年5月在《新英格兰医学杂志》上发表的一项2期试验评估了zodasiran治疗混合性高脂血症的效果。结果显示Zodasiran在混合型高脂血症患者中显示出显著降低TG、非HDL-C、载脂蛋白B和LDL-C水平的效果。其疗效呈现出剂量依赖性，200 mg剂量组的疗效最为显著。此外，Zodasiran治疗还与肝脏脂肪含量的减少相关。Zodasiran的整体安全性良好，未发现与药物相关的严重不良事件，但需注意在已存在糖尿病的患者中可能出现的糖化血红蛋白水平升高问题。 不过，根据Firece网站的最新报道，在资金流的压力下，Arrowhead Pharmaceuticals正在面临对两款心脏代谢疾病候选药物进行抉择，他们暂时需要放弃zodasiran，以便能全力支持另一个候选药物plzasiran的开发。不过，虽然Arrowhead计划倾全司之力在2025年将plzasiran推向市场，但仍希望能找到一个合作伙伴，来开发已经失去优先地位的zodasiran。 Ionis/诺华：Pelacarsen 作用机制：LP(a)抑制剂 适应症:主动脉瓣狭窄;心血管疾病;高脂蛋白血症2030年销售额预测：25.78亿美元（根据cortellis） Pelacarsen是一款反义寡核苷酸（ASO）药物，靶向Apo(a) mRNA，抑制其翻译成脂蛋白(a)的蛋白。其原研是IONIS，2019年和Norvartis达成合作协议共同开发。2023年初，Royalty Pharma买入IONIS持有的Pelacarsen的剩余权益的25%。目前Pelacarsen已完成I期与II期的临床研究。II期研究表明，Pelacarsen 20 mg QW降低Lp(a)最高可达80%，80mg/月的给药剂量可使98%的患者Lp(a)水平降至50 mg/dL以下。 III期试验（NCT04023552）主要观察其对心血管疾病患者的主要心血管事件的影响，该临床试验正在进行中。Pelacarsen将有望成为首个靶向强效降低脂蛋白(a)并带来心血管获益的药物。根据cortellis预测，Pelacarsen2030年销售额有望达到25.78亿美元。 Ionis/GSK：Bepirovirsen 作用机制：抑制HBsAg 蛋白表达，TLR8刺激免疫应答 适应症：乙肝销售峰值预测：25亿美元（根据GSK）Bepirovirsen (GSK3228836，GSK836) 是Ionis Pharmaceuticals 和 葛兰素史克（GSK）合作开发用于慢性乙型肝炎治疗的一款具有三重作用机制的非结合型反义寡核苷酸（ASO），靶向所有HBV RNA，包括HBV信使RNA和前基因组RNA，目前正在进行3期临床试验。该药物是目前唯一一款处在 phase III 期临床试验阶段的单药，与口服的核苷（酸）类似物联合用药时具有实现有临床意义的功能性治愈潜能。公司已公布phase IIb 期试验 B-Clear 和 B-Sure 的研究数据，这两项试验评估了 Bepirovirsen 对慢性乙型肝炎患者的疗效、安全性和反应持久性。一项确认疗效的III期临床试验B-Well正在进行中。在B-Clear试验中，总计457名慢性乙肝患者接受了不同剂量的bepirovirsen的治疗，其中大约一半同时在接受核苷/核苷酸类似物（NA）治疗，另一半没有接受NA治疗。研究结果显示，接受300毫克bepirovirsen治疗24周后，大约有26%~29%的患者的乙肝表面抗原和乙肝病毒DNA水平都低于可检测的最低水平。为期24周的随访观察显示，停药24周后，9%~10%的患者仍然维持乙肝表面抗原和乙肝病毒DNA水平检测不到的状态。在这些停药24周仍然维持乙肝表面抗原和乙肝病毒DNA水平检测不到的患者中，一半患者显示免疫系统被激活。目前，Bepirovirsen已相继获得中美日三国的 “快速通道”，这将大大缩短药物上市时间。 Ionis/渤健：BIIB080 作用机制：tau蛋白抑制剂 适应症：阿尔兹海默症 2030年销售额预测：20亿美元（根据Morningstar） BIIB080（IONIS-MAPT）是一款在研反义寡核苷酸（ASO）疗法，是首款进入临床试验期的tau蛋白靶向治疗轻度AD的ASO药物。BIIB080通过与编码tau蛋白的mRNA结合，导致mRNA的降解和tau蛋白水平的下降。在2023年10月举办的第 16 届阿尔茨海默病临床试验(CTAD)会议上，渤健公布了BIIB080的1b期试验临床积极结果。分析显示，接受该疗法患者展现认知下降改善的趋势。根据此积极结果，渤健已启动相关CELIA临床2期试验。 根据投资机构Morningstar的预测，预计BIIB080 的获批概率为30%，到 2030 年的概率加权销售额为 20 亿美元。 Alnylam/罗氏：zilebesiran 作用机制：血管紧张素原配体抑制剂 适应症:高血压销售峰值预测：19亿美元（根据Cortellis） Zilebesiran（ALN-AGT01）是一种皮下给药、靶向血管紧张素原（AGT）的在研RNAi治疗药物。AGT是肾素-血管紧张素-醛固酮系统（RAAS）中最上游的靶点，该级联反应已被证实在血压调节中发挥作用，其抑制具有明确的抗高血压作用。 zilebesiran的KARDIA-2临床研究数据表明：对于高血压控制不佳患者，zilebesiran与标准降压药联用，可带来额外的降压获益，降压效果可维持6个月。KARDIA-3 Ⅱ期研究(NCT06272487)已经启动，将评估zilebesiran对经2~4个标准降压药物治疗后血压仍不能有效控制的高血压患者的有效性和安全性，这些高血压患者同时存在慢性肾功能不全，或心血管疾病高危风险。Cortellis预测Zilebesiran 的潜在峰值销售额将达到 19 亿美元。 Ultragenyx：GTX-102 作用机制：UBE3A抑制剂 适应症:天使综合征2030年销售额预测：16.13亿美元（根据Cortellis） GTX-102是一款鞘内给药的在研反义寡核苷酸新药，旨在靶向和抑制UBE3A反义（UBE3A-AS）转录本的表达，同时激活神经元细胞中父系UBE3A的等位基因表达，产生患者体内所缺失的关键蛋白产物。该药物用于治疗天使综合征，这是由UBE3A基因缺失或突变导致的罕见性神经遗传疾病，患者会出现发育迟缓，平衡障碍、运动障碍以及癫痫发作等情况，大多不会说话。天使综合征经常被误诊为自闭症或脑瘫。目前尚未批准用于该疾病的疗法上市。 4月15日，Ultragenyx Pharmaceutical宣布了其用于治疗天使综合征（Angelman syndrome）的在研疗法GTX-102在1/2期临床试验中取得积极数据：接受GTX-102治疗的扩展队列A和B的患者，在第170天显示出具有临床意义的多领域功能改善。部分剂量递增队列患者在第758天显示出长期和持续的临床益处，远超过自然历史数据。根据cortellis预测，GTX-102在2030年销售额有望达到16.13亿美元。 再生元/Alnylam：Cemdisiran 作用机制：C5抑制剂 适应症:IgA肾病2030年销售额预测：11.67亿美元（根据Cortellis） Cemdisiran为一款再生元与Alnylam联合开发的C5靶向siRNA疗法。在IgA肾病中，补体系统的异常激活会导致过敏毒素C3a和C5a以及攻膜复合物C5b-9的过量产生，这些物质会损害肾小球结构。Cemdisiran通过精准靶向补体途径的关键成分——C5补体蛋白，有效阻断补体通路的激活，进而降低对肾脏的损害，并显著减少蛋白尿的排泄。 Cemdisiran 治疗IgA肾病的II期试验结果表明其可抑制肝脏中C5的产生，并能显著降低IgA肾病患者的尿蛋白水平。2024年8月13日，III期临床试验（R3918-MG-2018）完成首例给药。根据cortellis预测，cemdisiran2030年销售额有望达到11.67亿美元。 3）其他值得重点关注的重磅「活跃」药物 Arrowhead：plozasiran 作用机制：ApoC3抑制剂 适应症:I型高脂蛋白血症;高甘油三酯血症;脂质代谢紊乱2030年销售额预测：6.67亿美元（根据Cortellis） Plozasiran（ARO-APOC3）是Arrowhead公司首款研究性RNA干扰(RNAi)治疗药物，是一款靶向APOC3基因的潜在“first-in-class”RNAi疗法。Plozasiran治疗目标是通过下调APOC3降低甘油三酯水平，并将脂质恢复到更正常的水平。在多项临床研究中，plozasiran显示可降低FCS、严重高甘油三酯血症（SHTG）和混合性高脂血症患者的甘油三酯和多种致动脉粥样硬化脂蛋白。 2024年9月，Arrowhead Pharmaceuticals公布plozasiran用于治疗家族性乳糜微粒血症综合征（FCS）患者的3期PALISADE研究结果。分析显示，试验成功达到主要终点和所有关键次要终点，plozasiran使患者的甘油三酯（TG）、载脂蛋白C-III（APOC3）水平显著下降，并使急性胰腺炎（AP）的发病率显著降低。基于该试验积极数据，Arrowhead打算在2024年底前向美国FDA提交plozasiran的新药申请，并计划随后向其他全球监管机构寻求批准。 Wave Life Sciences：WVE-003 作用机制：HTT抑制剂 适应症：亨廷顿病 2030年销售额预测：4.52亿美元（根据Cortellis） 亨廷顿病是由于编码亨廷顿蛋白的HTT基因上出现CAG扩增，导致生成的亨廷顿蛋白突变体（mHTT）产生神经毒性。野生型亨廷顿蛋白对正常神经元功能也具有重要作用，因此HTT基因的突变不但增加了mHTT的产生，也降低了正常蛋白的水平，导致神经突触功能失常、细胞死亡和神经退行性病变。WWE-003是一款潜在“first-in-class”等位基因特异性RNAi疗法，它选择性结合表达mHTT的mRNA，在降低突变蛋白表达的同时，不影响野生型蛋白的表达。 6月26日，Wave Life Sciences宣布，在研疗法WVE-003在治疗亨廷顿病（HD）的1b/2a期临床试验SELECT-HD中取得了积极成果。数据显示，WVE-003总体安全性和耐受性良好，没有报告严重不良事件（SAEs），脑室体积与自然历史一致。在28周评估期间观察到WVE-003组患者显著的mHTT蛋白水平降低，支持每季度或更少频率的给药。在28周评估期间，wtHTT蛋白水平得到维持，验证了等位基因选择性沉默。此外，与安慰剂相比，wtHTT蛋白水平显著增加。 Ionis：donidalorsen 作用机制：激肽释放酶（PKK）抑制剂 适应症:遗传性血管性水肿（HAE）2030年销售额预测：3.90亿美元（根据Cortellis） Donidalorsen是一款潜在“first-in-class”的RNA反义寡核苷酸配体偶联（LICA）药物，旨在精确靶向以沉默前激肽释放酶（PKK）的表达，中断导致遗传性血管性水肿（HAE）发作的通路。PKK在激活与HAE急性发作相关的炎症介质中起重要作用。通过沉默PKK的产生，donidalorsen可能是治疗HAE的有效预防方法。IONIS授权日本大冢制药负责亚太地区和欧洲的特定区域开发、监管备案和商业化。 今年6月，Ionis公布了donidalorsen在治疗遗传性血管性水肿（HAE）的3期临床试验OASIS-HAE和OASISplus中的积极成果：donidalorsen以每月和每两月的给药方案进行治疗，一年后患者的HAE发作频率显著且持续降低超过90%；从其他预防性治疗转换至donidalorsen治疗的患者，其月均HAE发作率相较于基线进一步降低了62%，其中84%的患者更倾向于使用donidalorsen。Ionis 计划今年向美国食品药品管理局（FDA）提交新药申请，如获批准，将在美国独立上市donidalorsen。 PepGen：PGN-EDO51 作用机制：外显子51跳跃疗法 适应症:DMD 2030年销售额预测：2.79亿美元（根据Cortellis） PGN-ED051专门设计用于跳过外显子51，能够帮助大约13%的DMD患者。PepGen认为与现有药物相比，PGN-ED051的不同之处在于它使用了该公司专有的增强递送寡核苷酸技术，将药物直接递送至肌肉细胞，可以更有效地跳过外显子：与所有已获批准药物和已知开发中的候选药物相比，根据公开的跨研究数据，PGN-EDO51在灵长类动物的骨骼肌和隔膜中实现了最高的第51外显子跳跃水平，并且此效果在安全的剂量范围内获得。 今年8月，PepGen发布了其新式候选药物PGN-EDO51的积极临床数据：5mg/kg剂量的PGN-EDO51在三个月给药后，能使患者的外显子跳跃水平高于类似PMO剂量水平的其他寡核苷酸疗法。同时，此药物在肌肉调整后的肌营养不良蛋白水平上，也表现出较基线的显著增长。该公司计划在今后的试验中继续评估PGN-EDO51的疗效，并将着力于推动其二期试验CONNECT2-EDO51的开展。他们期待在更高剂量（10 mg/kg）中观察到更高水平的肌营养不良蛋白产生。 Idera Pharmaceuticals：Tilsotolimod 作用机制：TLR9激动剂 适应症：黑色素瘤2030年销售额预测：/ 在先天性免疫反应的过程中，TLR9扮演着举足轻重的角色，尤其在向肿瘤组织募集T细胞的过程中发挥着关键作用。这一靶点深藏于细胞内部，这使得TLR9激动剂的开发面临重重挑战，以寡核苷酸为药物形式的TLR9激动剂正逐渐成为研究热点。 Tilsotolimod 是一种在研合成 Toll 样受体 9 (TLR9) 激动剂，由Idera Pharmaceuticals开发，获得了美国FDA的快速通道，联合Ipilimumab用于治疗抗PD-1抗体难治性黑色素瘤，以及孤儿药物资格指定用于治疗IIb-IV期黑色素瘤。在I/II期临床试验中，ORR为22%，疾病控制率为71%，中位总生存期(OS)为21个月。目前处于黑色素瘤的关键3期临床（NCT03445533）阶段。 参考资料：医药魔方Info、摩熵医药、新康界、细胞基因治疗前沿 *文章封面首图及配图，版权归版权所有人所有。若版权者认为其作品不宜供大家浏览或不应无偿使用，请及时联系我们，本平台将立即更正。 SHINE CONSULTANT 上海士研管理咨询有限公司成立于2005年，致力于为组织领导者提供沟通交流与专家智库平台。通过二十年沉淀与积累，覆盖了金融与投资、交通与运输、消费与文旅、医药与医疗、能源与资源、高科与电信、公用与政府等产业领域，服务着全球500强和万余家领导型企业，汇聚了百万余名机构决策者，并与千余家产业权威机构建立了战略伙伴关系。士研咨询秉承专业立身的理念发展队伍，现拥有百余名专业的资深人员，核心管理团队都具有十五年以上的专业经验。

Third quarter 2024 revenues increased 11% to $3.72 billion versus third quarter 2023Third quarter 2024 Dupixent® global net sales (recorded by Sanofi) increased 23% to $3.82 billion versus third quarter 2023Third quarter 2024 U.S. net sales for EYLEA HD® and EYLEA® increased 3% versus third quarter 2023 to $1.54 billion, including $392 million from EYLEA HDThird quarter 2024 Libtayo® global net sales increased 24% to $289 million versus third quarter 2023Third quarter 2024 GAAP diluted EPS increased 30% to $11.54 and non-GAAP diluted EPS(a) increased 8% to $12.46 versus third quarter 2023; third quarter 2024 includes unfavorable $0.43 impact from acquired IPR&D chargeFDA approved Dupixent as first-ever biologic therapy in U.S. for treatment of inadequately controlled chronic obstructive pulmonary disease (COPD) and an eosinophilic phenotypePositive results reported for Dupixent pivotal trials in chronic spontaneous urticaria (CSU) and bullous pemphigoid (BP); CSU sBLA resubmitted and BP sBLA submission planned for fourth quarter 2024 TARRYTOWN, N.Y., Oct. 31, 2024 (GLOBE NEWSWIRE) -- Regeneron Pharmaceuticals, Inc. (NASDAQ: REGN) today announced financial results for the third quarter of 2024 and provided a business update. "Regeneron had a strong third quarter marked by 11% revenue growth. We continued to deepen the impact of our commercialized medicines this quarter, with ongoing leadership for our retinal franchise, expanded global reach of Libtayo, and notable growth from Dupixent," said Leonard S. Schleifer, M.D., Ph.D., Board co-Chair, President and Chief Executive Officer of Regeneron. "Over one million patients around the globe are currently being treated with Dupixent, with more to come following the approvals for COPD in the U.S., Europe and China. Our remarkably diverse clinical portfolio now includes approximately 40 product candidates and many pivotal studies underway. We continue to invest in the world-class research and development engine that drives our scientific and clinical productivity, with data expected over the next twelve months in diseases as varied as non-small cell lung cancer, thrombosis, retinal vein occlusion, severe allergy, COPD, melanoma, and obesity." Financial Highlights ($ in millions, except per share data) Q3 2024 Q3 2023 % ChangeTotal revenues $3,721 $3,363 11%GAAP net income $1,341 $1,008 33%GAAP net income per share - diluted $11.54 $8.89 30%Non-GAAP net income(a) $1,462 $1,329 10%Non-GAAP net income per share - diluted(a) $12.46 $11.59 8% "Our strong third quarter financial performance was highlighted by double-digit revenue growth and continued investment in our growing pipeline," said Christopher Fenimore, Senior Vice President, Finance and Chief Financial Officer of Regeneron. "We remain focused on translating cutting-edge science into differentiated medicines that have the greatest potential to serve patients, while deploying capital with the goal of maximizing shareholder returns, primarily through investing in innovation coupled with opportunistic share repurchases." Business Highlights Key Pipeline ProgressRegeneron has approximately 40 product candidates in clinical development, including a number of marketed products for which it is investigating additional indications. Updates from the clinical pipeline include: EYLEA HD (aflibercept) 8 mg The Company announced positive three-year (156-week) data from an extension study of the Phase 3 PHOTON trial in patients with diabetic macular edema (DME). At three years, the longer-term data showed the vast majority of EYLEA HD patients who entered the extension study sustained the visual gains and anatomic improvements achieved by the end of the second year. Of the EYLEA HD patients who completed the full 156 weeks of treatment, 48% were assigned a dosing interval of ≥20 weeks at the end of the third year. The results were presented at the American Academy of Ophthalmology (AAO) Annual Meeting. Dupixent (dupilumab) In September 2024, the U.S. Food and Drug Administration (FDA) approved Dupixent as an add-on maintenance treatment for adults with inadequately controlled COPD and an eosinophilic phenotype. With this approval, Dupixent is the first biologic medicine approved in the United States, European Union (EU), and China to treat these patients.In September 2024, the FDA approved Dupixent as an add-on maintenance treatment for adolescents aged 12 to 17 years with inadequately controlled chronic rhinosinusitis with nasal polyposis (CRSwNP).The European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion recommending expanded approval of Dupixent in the EU to treat children aged 1 to 11 years with eosinophilic esophagitis (EoE). The European Commission (EC) is expected to announce a final decision in the coming months.The Company and Sanofi announced that a confirmatory Phase 3 trial met the primary and key secondary endpoints for the investigational treatment of patients with uncontrolled, biologic-naïve CSU receiving background therapy with antihistamines, showing treatment with Dupixent resulted in a nearly 50% reduction in itch and urticaria activity scores from baseline. This positive trial confirms results from the first Phase 3 trial of Dupixent in this setting and these data supported the recent resubmission of a supplemental Biologics License Application (sBLA) to the FDA.The Company and Sanofi announced that a Phase 3 trial in bullous pemphigoid met the primary and all key secondary endpoints evaluating the investigational use in adults with moderate-to-severe disease. In the trial, five times more Dupixent patients achieved sustained disease remission compared to those on placebo. This trial will support global regulatory submissions, including the anticipated fourth quarter 2024 submission in the United States. Oncology Programs In August 2024, the EC approved Ordspono™ (odronextamab) to treat adult patients with relapsed or refractory (R/R) follicular lymphoma (FL) or R/R diffuse large B-cell lymphoma (DLBCL), after two or more lines of systemic therapy.The Company announced five-year results from the final pre-specified overall survival (OS) analysis of a Phase 3 trial, which evaluated Libtayo (cemiplimab) monotherapy versus chemotherapy as a first-line treatment for certain adults with advanced non-small cell lung cancer (NSCLC) with ≥50% PD-L1 expression. The results were presented at the IASLC 2024 World Conference on Lung Cancer.The Company submitted a regulatory application in Japan for Libtayo for first-line advanced NSCLC (monotherapy and chemotherapy combination).A Phase 2 study for Libtayo in neoadjuvant NSCLC was initiated.The Company presented new, two-year results at the European Society for Medical Oncology (ESMO) Annual Meeting, evaluating the investigational combination of fianlimab, an antibody to LAG-3, and Libtayo in adults with advanced melanoma across three independent expansion cohorts of a first-in-human, multi-cohort trial. These longer-term results show high clinical activity, including deepening responses, per a blinded independent central review.In August 2024, the FDA issued a Complete Response Letter (CRL) for the BLA for linvoseltamab, a bispecific antibody targeting BCMA and CD3, in R/R multiple myeloma that has progressed after at least three prior therapies. The sole approvability issue identified is related to findings from a pre-approval inspection at a third-party fill/finish manufacturer. Resolution of this issue will be required for both FDA and EC regulatory approvals. Other Programs A Phase 3 study was initiated for pozelimab, an antibody to C5, in combination with cemdisiran, an siRNA therapy, in geographic atrophy.A Phase 2 study for REGN7999, an antibody to TMPRSS6, for the treatment of iron overload in patients with beta-thalassemia was initiated. Third Quarter 2024 Financial Results Revenues ($ in millions) Q3 2024 Q3 2023 % ChangeNet product sales: EYLEA HD - U.S. $392 $43 *EYLEA - U.S. 1,145 1,448 (21%)Total EYLEA HD and EYLEA - U.S. 1,537 1,491 3%Libtayo - Global 289 232 25%Praluent® - U.S. 53 40 33%Evkeeza® - U.S. 32 19 68%Inmazeb® - Global 35 4 *Total net product sales 1,946 1,786 9% Collaboration revenue: Sanofi 1,263 1,065 19%Bayer 391 377 4%Other 6 (3) *Other revenue 114 138 (17%)Total revenues $3,720 $3,363 11% * Percentage not meaningful Total EYLEA HD and EYLEA net product sales in the U.S. increased 3% in the third quarter of 2024 compared to the third quarter of 2023. EYLEA HD was approved by the FDA in August 2023 and net product sales in the third quarter of 2024 were driven by the transition of patients from other anti-VEGF products, including EYLEA, as well as new patients naïve to anti-VEGF therapy. Net product sales of EYLEA in the third quarter of 2024 were adversely impacted by a lower net selling price compared to the third quarter of 2023. In addition, third quarter 2024 total EYLEA HD and EYLEA net product sales were favorably impacted by approximately $40 million as a result of higher wholesaler inventory levels for EYLEA HD at the end of the third quarter of 2024 compared to the end of the second quarter of 2024, partially offset by lower wholesaler inventory levels for EYLEA. Sanofi collaboration revenue increased in the third quarter of 2024, compared to the third quarter of 2023, due to an increase in the Company's share of profits from commercialization of antibodies, which were $1.09 billion in the third quarter of 2024, compared to $863 million in the third quarter of 2023. The change in the Company's share of profits from commercialization of antibodies was driven by higher profits associated with an increase in Dupixent sales. Sanofi collaboration revenue in the third quarter of 2023 was positively impacted by the recognition of the final $50 million sales-based milestone. Refer to Table 4 for a summary of collaboration revenue. Operating Expenses GAAP % Change Non-GAAP(a) % Change($ in millions) Q3 2024 Q3 2023 Q3 2024 Q3 2023 Research and development (R&D) $1,272 $1,075 18% $1,146 $954 20%Acquired in-process research and development (IPR&D) $56 $100 (44%) * * n/aSelling, general, and administrative (SG&A) $714 $641 11% $613 $534 15%Cost of goods sold (COGS) $262 $225 16% $217 $181 20%Cost of collaboration and contract manufacturing (COCM) $229 $212 8% * * n/aOther operating expense (income), net $8 $(1) ** $— * ** * GAAP and non-GAAP amounts are equivalent as no non-GAAP adjustments have been recorded.** Percentage not meaningful GAAP and non-GAAP R&D expenses increased in the third quarter of 2024, compared to the third quarter of 2023, driven by the advancement of the Company's clinical pipeline, including late-stage oncology programs, and higher headcount and headcount-related costs.Acquired IPR&D for the third quarter of 2024 included a $45 million development milestone in connection with the Company's collaboration agreement with Sonoma Biotherapeutics, Inc. Acquired IPR&D expense in the third quarter of 2023 related to a $100 million development milestone in connection with the Company's collaboration with Alnylam Pharmaceuticals, Inc.GAAP and non-GAAP SG&A expenses increased in the third quarter of 2024, compared to the third quarter of 2023, due to higher commercialization-related expenses to support the Company's launch of EYLEA HD and higher headcount and headcount-related costs partly related to the Company's international commercial expansion.GAAP and non-GAAP COGS increased in the third quarter of 2024, compared to the third quarter of 2023, primarily due to higher start-up costs for the Company's Rensselaer, New York fill/finish facility. Other Financial Information GAAP other income (expense) included the recognition of net unrealized gains on equity securities of $135 million in the third quarter of 2024, compared to $100 million of net unrealized losses in the third quarter of 2023. GAAP and Non-GAAP other income (expense) also included interest income of $187 million in the third quarter of 2024, compared to $134 million in the third quarter of 2023. In the third quarter of 2024, the Company's GAAP effective tax rate (ETR) was 10.2%, compared to 9.3% in the third quarter of 2023. The GAAP ETR increased in the third quarter of 2024, compared to the third quarter of 2023, due to a lower benefit from income earned in foreign jurisdictions with tax rates lower than the U.S. federal statutory rate. In the third quarter of 2024, the non-GAAP ETR was 10.7%, compared to 11.9% in the third quarter of 2023. GAAP net income per diluted share was $11.54 in the third quarter of 2024, compared to $8.89 in the third quarter of 2023. Non-GAAP net income per diluted share was $12.46 in the third quarter of 2024, compared to $11.59 in the third quarter of 2023. A reconciliation of the Company's GAAP to non-GAAP results is included in Table 3 of this press release. During the third quarter of 2024, the Company repurchased shares of its common stock and recorded the cost of the shares, or $738 million, as Treasury Stock. As of September 30, 2024, $2.9 billion remained available for share repurchases under the Company's share repurchase program. 2024 Financial Guidance(c) The Company's full year 2024 financial guidance consists of the following components: 2024 Guidance Prior UpdatedGAAP R&D $5.020–$5.170 billion $5.055–$5.145 billionNon-GAAP R&D(a) $4.500–$4.600 billion $4.525–$4.575 billionGAAP SG&A $2.920–$3.060 billion $2.930–$3.020 billionNon-GAAP SG&A(a) $2.550–$2.650 billion $2.550–$2.600 billionGAAP gross margin on net product sales(d) Approximately 86% UnchangedNon-GAAP gross margin on net product sales(a)(d) Approximately 89% UnchangedCOCM(e)* $850–$910 million $860–$900 millionCapital expenditures* $750–$820 million $700–$740 millionGAAP effective tax rate 8%–9% UnchangedNon-GAAP effective tax rate(a) 10%–11% Unchanged * GAAP and non-GAAP amounts are equivalent as no non-GAAP adjustments have been or are expected to be recorded. A reconciliation of full year 2024 GAAP to non-GAAP financial guidance is included below: Projected Range($ in millions) Low HighGAAP R&D $5,055 $5,145 Stock-based compensation expense 520 540 Acquisition and integration costs 10 30 Non-GAAP R&D $4,525 $4,575 GAAP SG&A $2,930 $3,020 Stock-based compensation expense 340 360 Acquisition, integration, and other costs 40 60 Non-GAAP SG&A $2,550 $2,600 GAAP gross margin on net product sales Approximately 86% Approximately 86%Stock-based compensation expense 1% 1%Intangible asset amortization expense 1% 1%Acquisition and integration costs <1% <1%Non-GAAP gross margin on net product sales Approximately 89% Approximately 89% GAAP ETR 8% 9%Income tax effect of GAAP to non-GAAP reconciling items 2% 2%Non-GAAP ETR 10% 11% (a)This press release uses non-GAAP R&D, non-GAAP SG&A, non-GAAP COGS, non-GAAP gross margin on net product sales, non-GAAP other operating (income) expense, net, non-GAAP other income (expense), net, non-GAAP ETR, non-GAAP net income, non-GAAP net income per share, total revenues excluding Ronapreve™(b), and free cash flow, which are financial measures that are not calculated in accordance with U.S. Generally Accepted Accounting Principles (GAAP). These non-GAAP financial measures are computed by excluding certain non-cash and/or other items from the related GAAP financial measure. The Company also includes a non-GAAP adjustment for the estimated income tax effect of reconciling items. A reconciliation of the Company's GAAP to non-GAAP results is included in Table 3 of this press release.The Company makes such adjustments for items the Company does not view as useful in evaluating its operating performance. For example, adjustments may be made for items that fluctuate from period to period based on factors that are not within the Company's control (such as the Company's stock price on the dates share-based grants are issued or changes in the fair value of the Company's investments in equity securities) or items that are not associated with normal, recurring operations (such as acquisition and integration costs). Management uses these non-GAAP measures for planning, budgeting, forecasting, assessing historical performance, and making financial and operational decisions, and also provides forecasts to investors on this basis. With respect to free cash flows, the Company believes that this non-GAAP measure provides a further measure of the Company's ability to generate cash flows from its operations. Additionally, such non-GAAP measures provide investors with an enhanced understanding of the financial performance of the Company's core business operations. However, there are limitations in the use of these and other non-GAAP financial measures as they exclude certain expenses that are recurring in nature. Furthermore, the Company's non-GAAP financial measures may not be comparable with non-GAAP information provided by other companies. Any non-GAAP financial measure presented by the Company should be considered supplemental to, and not a substitute for, measures of financial performance prepared in accordance with GAAP. (b)The casirivimab and imdevimab antibody cocktail for COVID-19 is known as REGEN-COV® in the United States and Ronapreve in other countries. Roche records net product sales of Ronapreve outside the United States. (c)The Company's 2024 financial guidance does not assume the completion of any business development transactions not completed as of the date of this press release. (d)Gross margin on net product sales represents gross profit expressed as a percentage of total net product sales recorded by the Company. Gross profit is calculated as net product sales less cost of goods sold. (e)Corresponding reimbursements from collaborators and others for manufacturing of commercial supplies is recorded within revenues. Conference Call Information Regeneron will host a conference call and simultaneous webcast to discuss its third quarter 2024 financial and operating results on Thursday, October 31, 2024, at 8:30 AM Eastern Time. Participants may access the conference call live via webcast, or register in advance and participate via telephone, on the "Investors and Media" page of Regeneron's website at www.regeneron.com. Upon registration, all telephone participants will receive a confirmation email detailing how to join the conference call, including the dial-in number along with a unique passcode and registrant ID that can be used to access the call. A replay of the conference call and webcast will be archived on the Company's website for at least 30 days. About Regeneron Pharmaceuticals, Inc. Regeneron is a leading biotechnology company that invents, develops, and commercializes life-transforming medicines for people with serious diseases. Founded and led by physician-scientists, Regeneron's unique ability to repeatedly and consistently translate science into medicine has led to numerous approved treatments and product candidates in development, most of which were homegrown in Regeneron's laboratories. Regeneron's medicines and pipeline are designed to help patients with eye diseases, allergic and inflammatory diseases, cancer, cardiovascular and metabolic diseases, neurological diseases, hematologic conditions, infectious diseases, and rare diseases. Regeneron pushes the boundaries of scientific discovery and accelerates drug development using its proprietary technologies, such as VelociSuite®, which produces optimized fully human antibodies and new classes of bispecific antibodies. Regeneron is shaping the next frontier of medicine with data-powered insights from the Regeneron Genetics Center® and pioneering genetic medicine platforms, enabling Regeneron to identify innovative targets and complementary approaches to potentially treat or cure diseases. For more information, please visit www.regeneron.com or follow Regeneron on LinkedIn, Instagram, Facebook, or X. Forward-Looking Statements and Use of Digital Media This press release includes forward-looking statements that involve risks and uncertainties relating to future events and the future performance of Regeneron Pharmaceuticals, Inc. ("Regeneron" or the "Company"), and actual events or results may differ materially from these forward-looking statements. Words such as "anticipate," "expect," "intend," "plan," "believe," "seek," "estimate," variations of such words, and similar expressions are intended to identify such forward-looking statements, although not all forward-looking statements contain these identifying words. These statements concern, and these risks and uncertainties include, among others, the nature, timing, and possible success and therapeutic applications of products marketed or otherwise commercialized by Regeneron and/or its collaborators or licensees (collectively, "Regeneron's Products") and product candidates being developed by Regeneron and/or its collaborators or licensees (collectively, "Regeneron's Product Candidates") and research and clinical programs now underway or planned, including without limitation EYLEA HD® (aflibercept) Injection 8 mg, EYLEA® (aflibercept) Injection, Dupixent® (dupilumab), Libtayo® (cemiplimab), Praluent® (alirocumab), Kevzara® (sarilumab), Evkeeza® (evinacumab), Veopoz® (pozelimab), Ordspono™ (odronextamab), itepekimab, fianlimab, garetosmab, linvoseltamab, REGN5713-5714-5715, nexiguran ziclumeran (NTLA-2001), Regeneron's other oncology programs (including its costimulatory bispecific portfolio), Regeneron's and its collaborators' earlier-stage programs, and the use of human genetics in Regeneron's research programs; the likelihood and timing of achieving any of the anticipated milestones described in this press release; safety issues resulting from the administration of Regeneron's Products and Regeneron's Product Candidates in patients, including serious complications or side effects in connection with the use of Regeneron’s Products and Regeneron's Product Candidates in clinical trials; the likelihood, timing, and scope of possible regulatory approval and commercial launch of Regeneron's Product Candidates and new indications for Regeneron's Products, including those listed above and/or otherwise discussed in this press release; the extent to which the results from the research and development programs conducted by Regeneron and/or its collaborators may be replicated in other studies and/or lead to advancement of product candidates to clinical trials, therapeutic applications, or regulatory approval; ongoing regulatory obligations and oversight impacting Regeneron's Products, research and clinical programs, and business, including those relating to patient privacy; determinations by regulatory and administrative governmental authorities which may delay or restrict Regeneron's ability to continue to develop or commercialize Regeneron's Products and Regeneron's Product Candidates; competing drugs and product candidates that may be superior to, or more cost effective than, Regeneron's Products and Regeneron's Product Candidates (including biosimilar versions of Regeneron's Products); uncertainty of the utilization, market acceptance, and commercial success of Regeneron's Products and Regeneron's Product Candidates and the impact of studies (whether conducted by Regeneron or others and whether mandated or voluntary) or recommendations and guidelines from governmental authorities and other third parties on the commercial success of Regeneron's Products and Regeneron's Product Candidates; the ability of Regeneron to manufacture and manage supply chains for multiple products and product candidates; the ability of Regeneron’s collaborators, suppliers, or other third parties (as applicable) to perform manufacturing, filling, finishing, packaging, labeling, distribution, and other steps related to Regeneron’s Products and Regeneron's Product Candidates; the availability and extent of reimbursement of Regeneron’s Products from third-party payers, including private payer healthcare and insurance programs, health maintenance organizations, pharmacy benefit management companies, and government programs such as Medicare and Medicaid; coverage and reimbursement determinations by such payers and new policies and procedures adopted by such payers; unanticipated expenses; the costs of developing, producing, and selling products; the ability of Regeneron to meet any of its financial projections or guidance and changes to the assumptions underlying those projections or guidance, including GAAP and non-GAAP R&D, GAAP and non-GAAP SG&A, GAAP and non-GAAP gross margin on net product sales, COCM, capital expenditures, and GAAP and non-GAAP ETR; the potential for any license or collaboration agreement, including Regeneron's agreements with Sanofi and Bayer (or their respective affiliated companies, as applicable), to be cancelled or terminated; the impact of public health outbreaks, epidemics, or pandemics (such as the COVID-19 pandemic) on Regeneron's business; and risks associated with intellectual property of other parties and pending or future litigation relating thereto (including without limitation the patent litigation and other related proceedings relating to EYLEA), other litigation and other proceedings and government investigations relating to the Company and/or its operations (including the pending civil proceedings initiated or joined by the U.S. Department of Justice and the U.S. Attorney's Office for the District of Massachusetts), the ultimate outcome of any such proceedings and investigations, and the impact any of the foregoing may have on Regeneron’s business, prospects, operating results, and financial condition. A more complete description of these and other material risks can be found in Regeneron's filings with the U.S. Securities and Exchange Commission, including its Form 10-K for the fiscal year ended December 31, 2023 and its Form 10-Q for the quarterly period ended September 30, 2024. Any forward-looking statements are made based on management's current beliefs and judgment, and the reader is cautioned not to rely on any forward-looking statements made by Regeneron. Regeneron does not undertake any obligation to update (publicly or otherwise) any forward-looking statement, including without limitation any financial projection or guidance, whether as a result of new information, future events, or otherwise. Regeneron uses its media and investor relations website and social media outlets to publish important information about the Company, including information that may be deemed material to investors. Financial and other information about Regeneron is routinely posted and is accessible on Regeneron's media and investor relations website (https://investor.regeneron.com) and its LinkedIn page (https://www.linkedin.com/company/regeneron-pharmaceuticals). Non-GAAP Financial Measures This press release and/or the financial results attached to this press release include amounts that are considered "non-GAAP financial measures" under SEC rules. As required, Regeneron has provided reconciliations of such non-GAAP financial measures. Contact Information: Ryan Crowe Christina ChanInvestor Relations Corporate Affairs914-847-8790 914-847-8827ryan.crowe@regeneron.com christina.chan@regeneron.com TABLE 1 REGENERON PHARMACEUTICALS, INC.CONDENSED CONSOLIDATED BALANCE SHEETS (Unaudited)(In millions) September 30, December 31, 2024 2023Assets: Cash and marketable securities $18,287.4 $16,241.3Accounts receivable, net 6,107.1 5,667.3Inventories 3,018.0 2,580.5Property, plant, and equipment, net 4,439.2 4,146.4Intangible assets, net 1,120.1 1,038.6Deferred tax assets 3,015.1 2,575.4Other assets 1,455.0 830.7Total assets $37,441.9 $33,080.2 Liabilities and stockholders' equity: Accounts payable, accrued expenses, and other liabilities $4,577.4 $3,818.6Finance lease liabilities 720.0 720.0Deferred revenue 834.6 585.6Long-term debt 1,984.0 1,982.9Stockholders' equity 29,325.9 25,973.1Total liabilities and stockholders' equity $37,441.9 $33,080.2 TABLE 2 REGENERON PHARMACEUTICALS, INC.CONDENSED CONSOLIDATED STATEMENTS OF OPERATIONS (Unaudited)(In millions, except per share data) Three Months Ended September 30, Nine Months Ended September 30, 2024 2023 2024 2023 Revenues: Net product sales $1,946.4 $1,786.1 $5,626.3 $5,226.2 Collaboration revenue 1,660.1 1,438.3 4,450.9 4,133.1 Other revenue 114.2 138.3 335.6 323.6 3,720.7 3,362.7 10,412.8 9,682.9 Expenses: Research and development 1,271.5 1,075.3 3,719.9 3,261.8 Acquired in-process research and development 56.2 100.0 87.2 156.1 Selling, general, and administrative 714.4 640.5 2,162.2 1,893.6 Cost of goods sold 262.3 224.5 760.5 625.3 Cost of collaboration and contract manufacturing 228.8 211.9 644.6 673.5 Other operating expense (income), net 8.0 (0.5) 37.9 (1.6) 2,541.2 2,251.7 7,412.3 6,608.7 Income from operations 1,179.5 1,111.0 3,000.5 3,074.2 Other income (expense): Other income (expense), net 327.3 17.6 866.0 32.2 Interest expense (13.8) (17.8) (44.7) (54.7) 313.5 (0.2) 821.3 (22.5) Income before income taxes 1,493.0 1,110.8 3,821.8 3,051.7 Income tax expense 152.4 103.0 326.9 257.7 Net income $1,340.6 $1,007.8 $3,494.9 $2,794.0 Net income per share - basic $12.40 $9.48 $32.36 $26.16 Net income per share - diluted $11.54 $8.89 $30.23 $24.57 Weighted average shares outstanding - basic 108.1 106.3 108.0 106.8 Weighted average shares outstanding - diluted 116.2 113.4 115.6 113.7 TABLE 3 REGENERON PHARMACEUTICALS, INC.RECONCILIATION OF GAAP TO NON-GAAP FINANCIAL INFORMATION (Unaudited)(In millions, except per share data) Three Months Ended September 30, Nine Months Ended September 30, 2024 2023 2024 2023 GAAP R&D $1,271.5 $1,075.3 $3,719.9 $3,261.8 Stock-based compensation expense 123.7 107.4 369.1 356.0 Acquisition and integration costs 2.0 13.5 11.1 17.7 Non-GAAP R&D $1,145.8 $954.4 $3,339.7 $2,888.1 GAAP SG&A $714.4 $640.5 $2,162.2 $1,893.6 Stock-based compensation expense 83.1 74.4 251.9 224.5 Acquisition, integration, and other costs 18.2 32.4 46.7 58.5 Non-GAAP SG&A $613.1 $533.7 $1,863.6 $1,610.6 GAAP COGS $262.3 $224.5 $760.5 $625.3 Stock-based compensation expense 18.3 22.1 57.4 64.1 Acquisition and integration costs 0.5 0.9 1.7 1.4 Intangible asset amortization expense 26.1 20.7 74.4 59.0 Charges related to REGEN-COV — — — (10.0)Non-GAAP COGS $217.4 $180.8 $627.0 $510.8 GAAP other operating expense (income), net $8.0 $(0.5) $37.9 $(1.6)Change in fair value of contingent consideration 8.0 — 37.9 — Non-GAAP other operating expense (income), net $— $(0.5) $— $(1.6) GAAP other income (expense), net $313.5 $(0.2) $821.3 $(22.5)(Gains) losses on investments, net (134.7) 127.0 (331.2) 324.5 Non-GAAP other income (expense), net $178.8 $126.8 $490.1 $302.0 GAAP net income $1,340.6 $1,007.8 $3,494.9 $2,794.0 Total of GAAP to non-GAAP reconciling items above 145.2 398.4 519.0 1,095.7 Income tax effect of GAAP to non-GAAP reconciling items (23.4) (77.1) (84.4) (211.5)Non-GAAP net income $1,462.4 $1,329.1 $3,929.5 $3,678.2 Non-GAAP net income per share - basic $13.53 $12.50 $36.38 $34.44 Non-GAAP net income per share - diluted $12.46 $11.59 $33.53 $31.90 Shares used in calculating: Non-GAAP net income per share - basic 108.1 106.3 108.0 106.8 Non-GAAP net income per share - diluted 117.4 114.7 117.2 115.3 RECONCILIATION OF GAAP TO NON-GAAP FINANCIAL INFORMATION (Unaudited) (continued) Three Months Ended September 30, Nine Months Ended September 30, 2024 2023 2024 2023 Revenue reconciliation: Total revenues $3,720.7 $3,362.7 $10,412.8 $9,682.9 Global gross profits earned in connection with sales of Ronapreve 0.5 — 1.4 222.2 Other — (5.7) — (9.5)Total revenues excluding Ronapreve $3,720.2 $3,368.4 $10,411.4 $9,470.2 Effective tax rate reconciliation: GAAP ETR 10.2% 9.3% 8.6% 8.4%Income tax effect of GAAP to non-GAAP reconciling items 0.5% 2.6% 0.9% 2.9%Non-GAAP ETR 10.7% 11.9% 9.5% 11.3% Nine Months Ended September 30, 2024 2023 Free cash flow reconciliation: Net cash provided by operating activities $3,157.7 $3,504.3 Capital expenditures (556.3) (467.2) Free cash flow $2,601.4 $3,037.1 TABLE 4 REGENERON PHARMACEUTICALS, INC.COLLABORATION REVENUE (Unaudited)(In millions) Three Months Ended September 30, Nine Months Ended September 30, 2024 2023 2024 2023 Sanofi collaboration revenue: Regeneron's share of profits in connection with commercialization of antibodies $1,088.3 $863.0 $2,880.6 $2,250.6 Sales-based milestones earned — 50.0 — 50.0 Reimbursement for manufacturing of commercial supplies 175.1 151.5 438.2 506.0 Total Sanofi collaboration revenue 1,263.4 1,064.5 3,318.8 2,806.6 Bayer collaboration revenue: Regeneron's share of profits in connection with commercialization of EYLEA 8 mg and EYLEA outside the United States 367.6 349.9 1,054.5 1,031.0 Reimbursement for manufacturing of ex-U.S. commercial supplies 23.2 27.2 67.4 79.7 Total Bayer collaboration revenue 390.8 377.1 1,121.9 1,110.7 Other collaboration revenue: Global gross profits earned from Roche in connection with sales of Ronapreve 0.5 — 1.4 222.2 Other 5.4 (3.3) 8.8 (6.4) Total collaboration revenue $1,660.1 $1,438.3 $4,450.9 $4,133.1 TABLE 5 REGENERON PHARMACEUTICALS, INC.NET PRODUCT SALES OF REGENERON-DISCOVERED PRODUCTS (Unaudited)(In millions) Three Months Ended September 30, 2024 2023 % Change U.S. ROW(g) Total U.S. ROW Total (Total Sales)EYLEA HD and EYLEA(a) $1,536.9 $931.7 $2,468.6 $1,490.9 $872.2 $2,363.1 4%Dupixent(b) $2,824.7 $992.5 $3,817.2 $2,366.3 $731.3 $3,097.6 23%Libtayo(c) $194.5 $94.1 $288.6 $144.1 $88.3 $232.4 24%Praluent(d) $52.9 $138.5 $191.4 $40.4 $125.1 $165.5 16%Kevzara(b) $72.7 $47.4 $120.1 $52.4 $43.3 $95.7 25%REGEN-COV(e) $— $1.2 $1.2 $— $— $— *Other products(f) $68.2 $23.2 $91.4 $23.4 $15.5 $38.9 135% Nine Months Ended September 30, 2024 2023 % Change U.S. ROW Total U.S. ROW Total (Total Sales)EYLEA HD and EYLEA(a) $4,473.2 $2,688.9 $7,162.1 $4,424.8 $2,605.6 $7,030.4 2%Dupixent(b) $7,652.9 $2,797.5 $10,450.4 $6,369.6 $2,002.4 $8,372.0 25%Libtayo(c) $536.1 $313.8 $849.9 $384.0 $241.0 $625.0 36%Praluent(d) $179.0 $405.6 $584.6 $121.1 $330.6 $451.7 29%Kevzara(b) $187.8 $136.1 $323.9 $148.5 $125.2 $273.7 18%REGEN-COV(e) $— $3.5 $3.5 $— $613.2 $613.2 (99%)Other products(f) $124.4 $61.7 $186.1 $64.0 $48.9 $112.9 65% Note: The table above includes net product sales of Regeneron-discovered products. Such net product sales are recorded by the Company or others, as further described in the footnotes below.* Percentage not meaningful(a) The Company records net product sales of EYLEA HD and EYLEA in the United States, and Bayer records net product sales outside the United States. The Company records its share of profits in connection with sales outside the United States within Collaboration revenue.(b) Sanofi records global net product sales of Dupixent and Kevzara, and the Company records its share of profits in connection with global sales of such products within Collaboration revenue.(c) The Company records global net product sales of Libtayo and pays Sanofi a royalty on such sales. Prior to July 1, 2022, Sanofi recorded net product sales of Libtayo outside the United States. Included in this line item for the nine months ended September 30, 2023 is approximately $6 million of first quarter 2023 net product sales recorded by Sanofi in connection with sales in certain markets outside the United States (Sanofi recorded net product sales in such markets during a transition period).(d) The Company records net product sales of Praluent in the United States. Sanofi records net product sales of Praluent outside the United States and pays the Company a royalty on such sales, which is recorded within Other revenue.(e) Roche records net product sales outside the United States and the Company records its share of gross profits from sales, which is recorded within Collaboration revenue.(f) Included in this line item are products which are sold by the Company and others. Refer to "Third Quarter 2024 Financial Results" section above for a complete listing of net product sales recorded by the Company. Not included in this line item are net product sales of ARCALYST®, which are recorded by Kiniksa; net product sales of ARCALYST were $103 million for the second quarter of 2024.(g) Rest of world (ROW)