Evinacumab-dgnb

Abstract 他汀类药物二十多年来一直是高胆固醇血症的一线治疗药物，当单用他汀无法达到低密度脂蛋白胆固醇（LDL-C）目标时，会联合依折麦布。然而，他汀和其他口服小分子药物常不足以使LDL-C达标。本综述描述了为克服与未控LDL-C相关的残余心血管风险而生产的单克隆抗体（mAb）。近年来，靶向前蛋白转化酶枯草溶菌素9（PCSK9）的mAb阿利珠单抗和依洛尤单抗已在全球确立为对他汀和依折麦布治疗后仍未达LDL-C目标患者的附加治疗，或有时作为他汀不耐受患者的替代治疗。它们已被证明在降低高危患者心血管事件方面安全有效。近期，中国研发并批准了四种靶向PCSK9的新mAb。其中一些mAb具有皮下给药频率更低的优势，一些为人源化mAb，其长期疗效是否保持尚待观察。新药物靶点被确定以潜在地降低升高的甘油三酯水平，并且发现mAb血管生成素样3（ANGPTL3）抑制剂evinacumab能有效降低纯合子家族性高胆固醇血症（FH）患者的LDL-C，并已获批该适应症。SHR-1918是另一个在中国研发的靶向ANGPTL3的mAb，可能也对治疗纯合子FH有效。这些药物昂贵，可能不适合更广泛的适应症，目前正在研发的反义寡核苷酸和小干扰RNA治疗可能更具成本效益。另一种处于早期研发阶段的mAb是靶向血管生成素样4（ANGPTL4）的MAR001。其作用尚待确定。 Introduction 动脉粥样硬化性心血管疾病（ASCVD）在美国及世界范围内仍是发病和死亡的主要原因，其驱动因素包括高血压、肥胖、2型糖尿病等主要风险因素的持续增加。高胆固醇血症，尤其是升高的LDL-C，是ASCVD的主要促成因素。他汀类药物通过抑制肝脏胆固醇内源性合成的限速酶3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶，已成为二十多年来降低LDL-C的主要治疗。他汀类药物通常耐受性良好，但对其肌肉症状和新增糖尿病风险的认识日益增加。许多观察性研究表明，尽管他汀类药物广泛可用，但大多数患者仍未达到LDL-C目标，原因包括处方惰性、依从性差等。依折麦布被推荐为他汀治疗后未达标者的下一添加治疗。近年来，贝派地酸作为另一种口服药物出现，可用于他汀治疗的替代或附加。 Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors 2003年PCSK9的发现为降低LDL-C的药物研发提供了新靶点。PCSK9功能获得性突变导致常染色体显性FH，而功能缺失性变异与较低的LDL-C水平和心血管事件减少相关。因此，抑制PCSK9成为降低LDL-C和心血管事件的有前景的替代方法。首批上市的PCSK9抑制剂是依洛尤单抗和阿利珠单抗，它们能使大多数患者的LDL-C降低约60%。Bococizumab是一种人源化mAb，但因在某些患者中产生抗药抗体而退出研发。近年来，中国批准了四种其他mAb。小干扰RNA（siRNA）inclisiran可每6个月皮下给药一次。其他类型的PCSK9抑制疗法也在研发中，包括口服药物enlicitide decanoate（MK-0616）和AZD0780、融合蛋白lerodalcibep以及CRISPR碱基编辑疗法VERVE-101/102。PCSK9靶向治疗通常对杂合子FH（HeFH）有效，但对纯合子FH（HoFH）效果有限。 Bococizumab Bococizumab是一种人源化IgG2Δa mAb。在SPIRE项目中，其心血管结局研究因其他研究中高抗药抗体发生率而提前终止。在较高风险、较长持续时间的试验中，主要心血管事件显著减少，但在较低风险、较短持续时间的试验中无影响。对6项临床试验的回顾发现，很大比例患者产生了抗药抗体，显著降低了LDL-C的降低幅度。 Evolocumab 依洛尤单抗是一种全人源IgG2 mAb，皮下给药剂量为140 mg每2周（Q2W）或420 mg每月（Q1M），可最大降低LDL-C约64%。它于2015年首次在全球获批。其消除遵循两相，涉及低浓度时与靶蛋白PCSK9的饱和结合和高浓度时的非饱和蛋白水解途径，估计有效半衰期（t1/2）为11至17天。在FOURIER试验中，依洛尤单抗将LDL-C水平较安慰剂降低了59%，并将复合心血管主要终点降低了15%。EBBINGHAUS亚研究表明，其认知功能无显著不良影响。 Alirocumab 阿利珠单抗是一种全人源IgG1 mAb，皮下给药剂量为75或150 mg Q2W，可降低LDL-C 45–62%。其绝对生物利用度约为85%，中位表观t1/2为17至20天。在ODYSSEY OUTCOMES心血管结局研究中，阿利珠单抗剂量根据LDL-C水平在75 mg和150 mg Q2W之间调整，使主要复合心血管终点降低了15%。其安全性与安慰剂相当，但注射部位反应更常见。即使LDL-C达到极低水平（如<25 mg/dL），也未发现认知测试差异。 Tafolecimab Tafolecimab（IBI306）是一种全人源IgG2 PCSK9 mAb，具有潜在长效作用。它于2023年在中国获批。其CREDIT系列3期研究显示，在非FH和高危患者中，能显著降低LDL-C（达65%），且耐受性良好。其药代动力学显示中位达峰时间（Tmax）约为4.7–7.5天，绝对生物利用度约58%，平均t1/2为26.1天。 Ongericimab Ongericimab（JS002）是一种重组抗PCSK9 mAb（描述存在人源化和全人源差异）。其3期试验表明，作为稳定降脂治疗的附加治疗，能显著且持续地降低LDL-C（达67.7%），并对其他血脂参数产生有利影响。在HoFH患者中的研究显示，其对LDLR缺陷型患者有效。 Ebronucimab Ebronucimab（AK102）是一种全人源IgG1 mAb，靶向PCSK9。其3期试验显示，与安慰剂相比，能有效降低LDL-C（约60%），且耐受性良好，主要不良反应为注射部位反应。 Recaticimab Recaticimab（SHR-1209）是一种人源化IgG1抗PCSK9 mAb，其Fc区引入了YTE基序以延长体内t1/2。其药代动力学显示t1/2（18.6至27.4天）长于依洛尤单抗和阿利珠单抗。3期研究REMAIN系列表明，其在不同给药间隔下均能有效降低LDL-C，且耐受性良好。 Angiopoietin-Like 3 (ANGPTL3) Inhibitors 血管生成素样蛋白（ANGPTLs）控制脂蛋白脂肪酶（LPL）在不同组织中的相对活性。ANGPTL3功能丧失性突变与低血浆甘油三酯浓度和联合低脂血症相关。因此，ANGPTL3成为降低甘油三酯和LDL-C的新治疗靶点。抑制ANGPTL3的策略包括mAb（如evinacumab、SHR-1918）、反义寡核苷酸（如vupanorsen）、siRNA（如zodasiran、solbinsiran）和CRISPR基因编辑系统（如CTX310、VERVE-201）。Vupanorsen因肝脂肪增加和肝酶升高而终止研发。 Evinacumab Evinacumab是一种全人源mAb（IgG4恒定区），通过结合循环中的ANGPTL3发挥作用，主要机制可能是增强LPL活性。它被FDA和EC批准用于HoFH。早期研究表明，其在HoFH患者中可降低LDL-C约49%，且该作用不依赖于LDL受体（LDLR）功能。其价格昂贵。在儿科HoFH患者中也显示出疗效。 SHR-1918 SHR-1918是一种靶向ANGPTL3的全人源mAb。其1期研究显示，单次皮下给药可显著降低LDL-C和甘油三酯，且作用持久。2期研究在合并高ASCVD风险的高脂血症患者中证实了其剂量和频率依赖性的降脂效果。针对HoFH的3期试验已启动。 Other ANGPTL Inhibitors ANGPTL4也被视为潜在治疗靶点，但其抑制在动物模型中与肠道及其引流淋巴管的脂质肉芽肿病变相关。MAR001是一种靶向ANGPTL4的人源化mAb，早期研究显示其能降低甘油三酯，且未观察到明显的系统性炎症或进行性淋巴结病变。LY3475766是一种靶向ANGPTL3/8复合物的mAb，能有效降低甘油三酯和LDL-C。 Conclusion 靶向PCSK9的全人源mAb依洛尤单抗和阿利珠单抗已确立地位，长期安全性良好，并有减少心血管事件的证据。它们对HeFH患者尤其有用，但对HoFH患者降低LDL-C效果有限。中国研发批准的四种PCSK9靶向mAb（tafolecimab、ebronucimab为全人源；ongericimab、recaticimab为人源化）尚未进行心血管结局研究。Recaticimab因YTE基序作用时间更长。人源化mAb是否会像bococizumab那样因抗药抗体导致疗效降低尚不确定。这些mAb价格昂贵， siRNA inclisiran可改善依从性但成本相似。口服PCSK9抑制剂若证明安全有效，可能成为有吸引力的替代方案。ANGPTL3已成为HoFH的治疗靶点。Evinacumab已获批该适应症，SHR-1918在中国研发中。它们能使HoFH患者的LDL-C降低约50%，虽可能不足以达标，但可减少脂蛋白血浆分离置换的需求。Evinacumab价格高昂，可能不用于其他适应症。SHR-1918效果相似，成本可能影响其应用广度。靶向ANGPTL4的MAR001处于研发早期，其作用待定。

Third quarter 2025 revenues increased 1% to $3.75 billion versus third quarter 2024Dupixent® global net sales (recorded by Sanofi) increased 27% to $4.86 billion EYLEA HD® U.S. net sales increased 10% to $431 million; total EYLEA HD and EYLEA® U.S. net sales decreased 28% to $1.11 billion GAAP EPS of $13.62 and non-GAAP EPS(a) of $11.83; third quarter 2025 includes unfavorable $0.68 impact from acquired IPR&D chargeFDA approved Libtayo® as the first and only immunotherapy for high-risk adjuvant cutaneous squamous cell carcinoma (CSCC); EMA's CHMP adopted positive opinionPositive Phase 3 results reported from trials in generalized myasthenia gravis, fibrodysplasia ossificans progressiva (FOP), and cat and birch allergies; updated positive data reported from pivotal trial in children with profound genetic hearing loss TARRYTOWN, N.Y., Oct. 28, 2025 (GLOBE NEWSWIRE) -- Regeneron Pharmaceuticals, Inc. (NASDAQ: REGN) today announced financial results for the third quarter of 2025 and provided a business update. "Regeneron had a solid financial quarter and made progress across our late-stage portfolio by securing new FDA approvals for Libtayo, Evkeeza, and Lynozyfic, receiving positive CHMP opinions for Libtayo and Dupixent, and sharing promising data across our oncology, obesity, allergy, and rare disease portfolios," said Leonard S. Schleifer, M.D., Ph.D., Board co-Chair, President and Chief Executive Officer of Regeneron. "We were proud to receive one of the FDA’s first Commissioner's National Priority Vouchers for DB-OTO for a rare form of congenital hearing loss. We also donated our Ebola treatment, Inmazeb, to countries most at risk of outbreaks, reflecting our commitment to ensuring patients in need are able to access our novel medicines." Financial Highlights ($ in millions, except per share data) Q3 2025 Q3 2024 % ChangeTotal revenues $3,754 $3,721 1% GAAP net income $1,460 $1,341 9% GAAP net income per share - diluted $13.62 $11.54 18% Non-GAAP net income(a) $1,287 $1,462 (12%)Non-GAAP net income per share - diluted(a) $11.83 $12.46 (5%) "We were pleased with our third quarter 2025 performance, which highlights the commercial strength of Dupixent, EYLEA HD, and Libtayo, and reinforces our momentum toward delivering solid financial performance for the year while advancing transformative therapies to patients around the world," said Christopher Fenimore, Executive Vice President, Finance and Chief Financial Officer of Regeneron. "Our disciplined approach to capital allocation fuels innovation through targeted investments, all while delivering value to shareholders. In the first nine months of 2025, we reaffirmed our commitment to advancing U.S. innovation and manufacturing by investing nearly $5 billion in R&D and capital expenditures, predominantly within the United States. We also returned over $3 billion to shareholders via share repurchases and dividends, underscoring our commitment to long-term value creation." Business Highlights Key Pipeline ProgressRegeneron has approximately 45 product candidates in clinical development, including a number of marketed products for which it is investigating additional indications. Updates from the clinical pipeline include: Dupixent (dupilumab) In September 2025, the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion recommending the approval of Dupixent in the European Union (EU) for the treatment of chronic spontaneous urticaria (CSU) in adults and adolescents aged 12 years and older who remain symptomatic despite antihistamine treatment. The European Commission (EC) is expected to announce a final decision in the coming months. EYLEA HD (aflibercept) 8 mg In October 2025, the Company was notified by Catalent Indiana, LLC (Catalent), the manufacturing filler in the EYLEA HD Biologics License Application (BLA), that they received an official action indicated (OAI) letter from the FDA citing unresolved issues related to a July 2025 FDA general site inspection (not specific to EYLEA HD). Yesterday, the FDA issued a Complete Response Letter (CRL) for the pre-filled syringe supplemental BLA (sBLA). The sole approvability issue cited in the CRL relates to unresolved inspection findings at Catalent. The Company is planning to submit by January 2026 an application to include a new pre-filled syringe manufacturing filler in the EYLEA HD BLA. There is also an sBLA under review by the FDA for EYLEA HD every-four-week dosing and for the treatment of macular edema following retinal vein occlusion (RVO), which has a target action date in late November 2025. In addition, the Company has submitted an application to include an additional vial filler, with an FDA decision regarding this new vial filler expected by late December 2025. Libtayo (cemiplimab) In October 2025, the FDA approved an sBLA for Libtayo as an adjuvant treatment for adults with CSCC at high risk of recurrence after surgery and radiation, making Libtayo the first and only immunotherapy approved in this setting. The EMA's CHMP also adopted a positive opinion for the adjuvant treatment of CSCC, and the EC is expected to announce a final decision in the coming months.In September 2025, Japan's Ministry of Health, Labour and Welfare (MHLW) approved Libtayo for an additional indication, as a monotherapy and in combination with chemotherapy for the treatment of adult patients with unresectable advanced or relapsed non-small cell lung cancer (NSCLC).In September 2025, the Company announced five-year follow-up results on overall survival from a Phase 3 trial, which evaluated Libtayo plus platinum-based chemotherapy versus chemotherapy alone as a first-line treatment for adults with locally advanced or metastatic NSCLC. The data demonstrate a more than double five-year overall survival rate of 19.4%, compared to 8.8% with chemotherapy alone, and was presented at the IASLC 2025 World Conference on Lung Cancer. Other Programs In August 2025, the Company announced that the primary and key secondary endpoints were met in a Phase 3 trial of cemdisiran (siRNA therapy), as both a monotherapy and in combination with pozelimab (C5 antibody), in adults with generalized myasthenia gravis. Cemdisiran monotherapy was numerically better than the combination treatment across these endpoints, showing a statistically significant 2.3-point placebo-adjusted improvement in Myasthenia Gravis Activities of Daily Living (MG-ADL) total score. A U.S. regulatory submission for cemdisiran monotherapy is planned for the first quarter of 2026, pending discussions with the FDA.In October 2025, updated data from the pivotal trial of DB-OTO, an AAV-based gene therapy, in children with profound genetic hearing loss due to variants of the otoferlin (OTOF) gene were published in the New England Journal of Medicine and presented at the annual American Academy of Otolaryngology-Head and Neck Surgery meeting. These latest results from the CHORD trial show 11 out of 12 participants have experienced clinically meaningful hearing improvements. A U.S. regulatory submission for DB-OTO is planned for the fourth quarter of 2025.In October 2025, the FDA selected DB-OTO to receive one of the Commissioner’s National Priority Vouchers, a pilot program intended to reduce the review time for certain drug and biologic applications to just one to two months.In September 2025, the Company announced the primary endpoint was met in a Phase 3 trial of garetosmab in adults with FOP, showing a 90% or greater reduction in new bone lesions (heterotopic ossification, or HO lesions) compared to placebo at 56 weeks, and a greater than 99% reduction in the total volume of new HO lesions. A U.S. regulatory submission for garetosmab is planned for the fourth quarter of 2025.In September 2025, the FDA approved Evkeeza® (evinacumab) for the treatment of homozygous familial hypercholesterolemia (HoFH), extending the already approved indication to include children from age 1 to less than 5 years old.In September 2025, the Company announced results from the Phase 3 trials evaluating its allergen-blocking antibodies in adults with moderate-to-severe cat allergies (REGN1908 and REGN1909) or birch allergies (REGN5713 and REGN5715). Both trials met their respective primary and key secondary endpoints, with single doses of the allergen-specific antibody blockers significantly reducing allergy symptoms compared to placebo at day 8. Additional Phase 3 development is planned to begin by the end of the year. Corporate Updates In September and October 2025, the Company reached resolution of its patent infringement litigation related to the Sandoz, Formycon, and Celltrion EYLEA (aflibercept) Injection 2 mg biosimilar products. The settlements preclude Sandoz, Formycon, and Celltrion from launching their biosimilar products in the United States until the fourth quarter of 2026. All intellectual property-related litigation with Sandoz, Formycon, and Celltrion in the United States has been dismissed. Third Quarter 2025 Financial Results Revenues ($ in millions) Q3 2025 Q3 2024 % ChangeNet product sales: EYLEA HD - U.S. $431 $392 10% EYLEA - U.S. 681 1,145 (41%)Total EYLEA HD and EYLEA - U.S. 1,112 1,537 (28%)Libtayo - U.S. 219 195 12% Libtayo - ROW* 146 94 55% Total Libtayo - Global 365 289 26% Praluent®- U.S. 67 53 26% Evkeeza - U.S. 43 32 34% Other products - Global 1 35 (97%)Total net product sales 1,588 1,946 (18%) Collaboration revenue: Sanofi 1,617 1,263 28% Bayer 345 391 (12%)Other 6 6 —% Other revenue 198 114 74% Total revenues $3,754 $3,720 1% * Rest of world (ROW) Net product sales of EYLEA HD increased in the third quarter of 2025, compared to the third quarter of 2024, due to higher sales volumes driven by increased demand, partly offset by a lower net selling price. Net product sales of EYLEA in the third quarter of 2025, compared to the third quarter of 2024, were negatively impacted by (i) lower sales volumes as a result of continued competitive pressures, loss in market share to compounded bevacizumab due to patient affordability constraints, and the continued transition of patients to EYLEA HD, and (ii) a lower net selling price. Sanofi collaboration revenue increased in the third quarter of 2025, compared to the third quarter of 2024, due to an increase in the Company's share of profits from the commercialization of antibodies, which were $1.46 billion and $1.09 billion in the third quarter of 2025 and 2024, respectively. 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. Refer to Table 4 for a summary of collaboration revenue. Other revenue increased in the third quarter of 2025, compared to the third quarter of 2024, due to an increase in royalties and share of profits earned in connection with license agreements, which were $165 million and $91 million for the third quarter of 2025 and 2024, respectively. Operating Expenses GAAP % Non-GAAP(a) %($ in millions) Q3 2025 Q3 2024 Change Q3 2025 Q3 2024 ChangeResearch and development (R&D) $1,475 $1,272 16% $1,350 $1,146 18%Acquired in-process research and development (IPR&D) $83 $56 48% * * n/a Selling, general, and administrative (SG&A) $658 $714 (8%) $541 $613 (12%)Cost of goods sold (COGS) $281 $262 7% $227 $217 5%Gross margin on net product sales(b) 82% 87% 86% 89% Cost of collaboration and contract manufacturing (COCM)(c) $241 $229 5% * * n/a Other operating (income) expense, net $(10) $8 ** * $— ** * 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 2025, compared to the third quarter of 2024, driven by the advancement of the Company's late-stage clinical pipeline.Acquired IPR&D expenses for the third quarter of 2025 included an $80 million up-front payment in connection with the Company's license agreement with Hansoh Pharmaceuticals Group Company Limited. Acquired IPR&D expenses for the third quarter of 2024 included a $45 million development milestone in connection with the Company's collaboration agreement with Sonoma Biotherapeutics, Inc.GAAP and non-GAAP SG&A expenses decreased in the third quarter of 2025, compared to the third quarter of 2024, primarily due to lower charitable contributions to an independent not-for-profit patient assistance organization.GAAP and non-GAAP gross margin on net product sales decreased in the third quarter of 2025, compared to the third quarter of 2024, partly due to ongoing investments to support the Company's manufacturing operations. In addition, GAAP gross margin on net product sales decreased due to higher amortization expense associated with the Company's Libtayo intangible asset. Other Financial Information GAAP other income (expense), net included the recognition of net gains on marketable and other securities of $578 million in the third quarter of 2025, compared to $135 million in the third quarter of 2024. In the third quarter of 2025, the Company's GAAP effective tax rate (ETR) was 17.2%, compared to 10.2% in the third quarter of 2024. The GAAP ETR increased in the third quarter of 2025, compared to the third quarter of 2024, primarily due to the impact of the enactment of the "One Big Beautiful Bill Act" or "OBBBA," including a $45 million charge related to the re-measurement of the Company's U.S. net deferred tax assets, as well as lower tax benefits from less stock option exercises. In the third quarter of 2025, the non-GAAP ETR was 13.1%, compared to 10.7% in the third quarter of 2024. A reconciliation of the Company's GAAP to non-GAAP results is included in Table 3 of this press release. Capital Allocation During the third quarter of 2025, the Company repurchased shares of its common stock and recorded the cost of the shares, or $663 million, as Treasury Stock. As of September 30, 2025, $2.156 billion remained available for share repurchases under the Company's share repurchase programs. In October 2025, the Company's board of directors declared a cash dividend of $0.88 per share on the Company's common stock and Class A stock, payable on December 5, 2025 to shareholders of record as of November 20, 2025. 2025 Financial Guidance* The Company's full year 2025 financial guidance consists of the following components: 2025 Guidance Prior UpdatedGAAP R&D $5.660–$5.790 billion $5.680–$5.750 billionNon-GAAP R&D(a) $5.100–$5.200 billion $5.150–$5.200 billionGAAP SG&A** $2.810–$2.940 billion $2.775–$2.845 billionNon-GAAP SG&A(a)** $2.450–$2.550 billion $2.400–$2.450 billionGAAP gross margin on net product sales Approximately 83% Approximately 82%Non-GAAP gross margin on net product sales(a) Approximately 86% UnchangedCOCM*** $1.000–$1.050 billion $950 million–$1.000 billionCapital expenditures*** $880–$950 million $850–$890 millionGAAP effective tax rate 11%–13% Approximately 14%Non-GAAP effective tax rate(a) 11%–13% Approximately 12% * The Company's 2025 financial guidance does not assume the completion of any business development transactions not completed as of the date of this press release** The Company's 2025 financial guidance includes potential matching program donations to Good Days, an independent national non-profit charitable organization, to support Good Days’ Retinal Vascular and Neovascular Disease Fund*** GAAP and non-GAAP amounts are equivalent as no non-GAAP adjustments have been or are expected to be recorded A reconciliation of full year 2025 GAAP to non-GAAP financial guidance is included below: Projected Range($ in millions) Low HighGAAP R&D $5,680 $5,750 Stock-based compensation expense 530 550 Non-GAAP R&D(a) $5,150 $5,200 GAAP SG&A $2,775 $2,845 Stock-based compensation expense 350 370 Litigation settlements 25 25 Non-GAAP SG&A(a) $2,400 $2,450 GAAP gross margin on net product sales 82% 82% Intangible asset amortization expense 2% 2% Stock-based compensation expense 1% 1% Other < 1% < 1% Non-GAAP gross margin on net product sales(a) 86% 86% GAAP ETR 14% 14% Income tax effect of GAAP to non-GAAP reconciling items 1% 1% Income tax expense: Charge related to enactment of OBBBA 1% 1% Non-GAAP ETR(a) 12% 12% (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, 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 flow, 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, the non-GAAP measures presented are intended to 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)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. (c)Corresponding reimbursements from collaborators and others for manufacturing product is recorded within revenues. Conference Call Information Regeneron will host a conference call and simultaneous webcast to discuss its third quarter 2025 financial and operating results on Tuesday, October 28, 2025, 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 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, competing drugs and product candidates that may be superior to, or more cost effective than, 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") (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 or other factors beyond Regeneron's control on the commercial success of Regeneron's Products and Regeneron's Product Candidates; the nature, timing, and possible success and therapeutic applications of Regeneron's Products and 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), Lynozyfic™ (linvoseltamab), other clinical programs discussed in this press release, 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; the ability of Regeneron to manufacture and manage supply chains for multiple products and product candidates and risks associated with tariffs and other trade restrictions; 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 or copay assistance for Regeneron’s Products from third-party payors and other third parties, including private payor 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 payors and other third parties and new policies and procedures adopted by such payors and other third parties; changes to drug pricing regulations and requirements and Regeneron's drug pricing strategy; other changes in laws, regulations, and policies affecting the healthcare industry; 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 on Regeneron's business; and risks associated with 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), 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), 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, 2024 and its Form 10-Q for the quarterly period ended September 30, 2025. 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 CroweChristina ChanInvestor RelationsCorporate Affairs914-847-8790914-847-8827ryan.crowe@regeneron.com christina.chan@regeneron.com TABLE 1 REGENERON PHARMACEUTICALS, INC.CONDENSED CONSOLIDATED BALANCE SHEETS (Unaudited)(In millions) September 30, December 31, 2025 2024Assets: Cash and marketable securities $18,729.3 $17,912.6 Accounts receivable, net 5,687.1 6,211.9 Inventories 3,254.4 3,087.3 Property, plant, and equipment, net 5,002.3 4,599.7 Intangible assets, net 1,380.9 1,148.6 Deferred tax assets 3,846.7 3,314.1 Other assets 2,268.7 1,485.2 Total assets $40,169.4 $37,759.4 Liabilities and stockholders' equity: Accounts payable, accrued expenses, and other liabilities $5,741.3 $4,888.0 Finance lease liabilities 720.0 720.0 Deferred revenue 764.8 813.4 Long-term debt 1,985.5 1,984.4 Stockholders' equity 30,957.8 29,353.6 Total liabilities and stockholders' equity $40,169.4 $37,759.4 TABLE 2 REGENERON PHARMACEUTICALS, INC.CONDENSED CONSOLIDATED STATEMENTS OF OPERATIONS (Unaudited)(In millions, except per share data) Three Months EndedSeptember 30, Nine Months EndedSeptember 30, 2025 2024 2025 2024 Revenues: Net product sales $1,587.7 $1,946.4 $4,634.3 $5,626.3 Collaboration revenue 1,968.4 1,660.1 5,360.3 4,450.9 Other revenue 198.2 114.2 464.0 335.6 3,754.3 3,720.7 10,458.6 10,412.8 Expenses: Research and development 1,475.0 1,271.5 4,224.1 3,719.9 Acquired in-process research and development 83.1 56.2 105.4 87.2 Selling, general, and administrative 657.8 714.4 1,925.0 2,162.2 Cost of goods sold 281.0 262.3 822.1 760.5 Cost of collaboration and contract manufacturing 240.6 228.8 694.0 644.6 Other operating (income) expense, net (10.0) 8.0 (10.0) 37.9 2,727.5 2,541.2 7,760.6 7,412.3 Income from operations 1,026.8 1,179.5 2,698.0 3,000.5 Other income (expense): Other income (expense), net 755.8 327.3 1,520.6 866.0 Interest expense (19.3) (13.8) (31.6) (44.7) 736.5 313.5 1,489.0 821.3 Income before income taxes 1,763.3 1,493.0 4,187.0 3,821.8 Income tax expense 303.3 152.4 526.7 326.9 Net income $1,460.0 $1,340.6 $3,660.3 $3,494.9 Net income per share - basic $14.09 $12.40 $34.83 $32.36 Net income per share - diluted $13.62 $11.54 $33.61 $30.23 Weighted average shares outstanding - basic 103.6 108.1 105.1 108.0 Weighted average shares outstanding - diluted 107.2 116.2 108.9 115.6 TABLE 3 REGENERON PHARMACEUTICALS, INC.RECONCILIATION OF GAAP TO NON-GAAP FINANCIAL INFORMATION (Unaudited)(In millions, except per share data) Three Months EndedSeptember 30, Nine Months EndedSeptember 30, 2025 2024 2025 2024 GAAP R&D $1,475.0 $1,271.5 $4,224.1 $3,719.9 Stock-based compensation expense 125.1 123.7 405.1 369.1 Acquisition and integration costs — 2.0 — 11.1 Non-GAAP R&D $1,349.9 $1,145.8 $3,819.0 $3,339.7 GAAP SG&A $657.8 $714.4 $1,925.0 $2,162.2 Stock-based compensation expense 92.0 83.1 279.0 251.9 Acquisition and integration costs — 8.2 0.8 36.7 Litigation settlements 25.0 10.0 25.0 10.0 Non-GAAP SG&A $540.8 $613.1 $1,620.2 $1,863.6 GAAP COGS $281.0 $262.3 $822.1 $760.5 Stock-based compensation expense 19.9 18.3 60.3 57.4 Acquisition and integration costs — 0.5 — 1.7 Intangible asset amortization expense 33.7 26.1 94.8 74.4 Non-GAAP COGS $227.4 $217.4 $667.0 $627.0 GAAP other operating (income) expense, net $(10.0) $8.0 $(10.0) $37.9 Change in fair value of contingent consideration — 8.0 — 37.9 Non-GAAP other operating (income) expense, net $(10.0) $— $(10.0) $— GAAP other income (expense), net $736.5 $313.5 $1,489.0 $821.3 Gains on marketable and other securities, net (577.7) (134.7) (967.6) (331.2)Non-GAAP other income (expense), net $158.8 $178.8 $521.4 $490.1 GAAP net income $1,460.0 $1,340.6 $3,660.3 $3,494.9 Total of GAAP to non-GAAP reconciling items above (282.0) 145.2 (102.6) 519.0 Income tax effect of GAAP to non-GAAP reconciling items 64.7 (23.4) 37.0 (84.4)Income tax expense: Charge related to enactment of OBBBA 44.5 — 44.5 — Non-GAAP net income $1,287.2 $1,462.4 $3,639.2 $3,929.5 Non-GAAP net income per share - basic $12.42 $13.53 $34.63 $36.38 Non-GAAP net income per share - diluted $11.83 $12.46 $32.87 $33.53 Shares used in calculating: Non-GAAP net income per share - basic 103.6 108.1 105.1 108.0 Non-GAAP net income per share - diluted 108.8 117.4 110.7 117.2 RECONCILIATION OF GAAP TO NON-GAAP FINANCIAL INFORMATION (Unaudited) (continued) Three Months EndedSeptember 30, Nine Months EndedSeptember 30, 2025 2024 2025 2024 Effective tax rate reconciliation: GAAP ETR 17.2% 10.2% 12.6% 8.6%Income tax effect of GAAP to non-GAAP reconciling items (2.4%) 0.5% (0.8%) 0.9%Income tax expense: Charge related to enactment of OBBBA (1.7%) —% (0.9%) —%Non-GAAP ETR 13.1% 10.7% 10.9% 9.5% Gross margin on net product sales reconciliation: GAAP gross margin on net product sales 82% 87% 82% 86%Intangible asset amortization expense 2% 1% 2% 2%Stock-based compensation expense 2% 1% 2% 1%Non-GAAP gross margin on net product sales 86% 89% 86% 89% Nine Months EndedSeptember 30, 2025 2024 Free cash flow reconciliation: Net cash provided by operating activities $3,808.2 $3,157.7 Capital expenditures (649.7) (556.3) Free cash flow $3,158.5 $2,601.4 TABLE 4 REGENERON PHARMACEUTICALS, INC.COLLABORATION REVENUE (Unaudited)(In millions) Three Months EndedSeptember 30, Nine Months EndedSeptember 30, 2025 2024 2025 2024Sanofi collaboration revenue: Regeneron's share of profits in connection with commercialization of antibodies $1,455.5 $1,088.3 $3,755.7 $2,880.6 Reimbursement for manufacturing of commercial supplies 161.5 175.1 488.1 438.2 Total Sanofi collaboration revenue 1,617.0 1,263.4 4,243.8 3,318.8 Bayer collaboration revenue: Regeneron's share of profits in connection with commercialization of EYLEA 8 mg and EYLEA outside the United States 311.9 367.6 1,012.6 1,054.5 Reimbursement for manufacturing of commercial supplies 32.9 23.2 91.1 67.4 Total Bayer collaboration revenue 344.8 390.8 1,103.7 1,121.9 Other collaboration revenue 6.6 5.9 12.8 10.2 Total collaboration revenue $1,968.4 $1,660.1 $5,360.3 $4,450.9 TABLE 5 REGENERON PHARMACEUTICALS, INC.NET PRODUCT SALES OF REGENERON-DISCOVERED PRODUCTS (Unaudited)(In millions) Three Months EndedSeptember 30, 2025 2024 % Change U.S. ROW Total U.S. ROW Total (Total Sales)EYLEA HD(a) $430.6 $232.4 $663.0 $392.3 $75.2 $467.5 42%EYLEA(a) $680.6 $621.4 $1,302.0 $1,144.6 $856.5 $2,001.1 (35%)Total EYLEA HD and EYLEA $1,111.2 $853.8 $1,965.0 $1,536.9 $931.7 $2,468.6 (20%)Dupixent(b) $3,618.8 $1,238.2 $4,857.0 $2,824.7 $992.5 $3,817.2 27%Libtayo(c) $219.1 $146.1 $365.2 $194.5 $94.1 $288.6 27%Praluent(d) $67.7 $148.0 $215.7 $52.9 $138.5 $191.4 13%Kevzara(b) $102.9 $51.1 $154.0 $72.7 $47.4 $120.1 28%Other products(e) $43.9 $28.0 $71.9 $68.2 $24.4 $92.6 (22%) Nine Months EndedSeptember 30, 2025 2024 % Change U.S. ROW Total U.S. ROW Total (Total Sales)EYLEA HD(a) $1,130.6 $620.5 $1,751.1 $896.5 $149.5 $1,046.0 67%EYLEA(a) $2,170.9 $2,068.8 $4,239.7 $3,576.7 $2,539.4 $6,116.1 (31%)Total EYLEA HD and EYLEA $3,301.5 $2,689.3 $5,990.8 $4,473.2 $2,688.9 $7,162.1 (16%)Dupixent(b) $9,453.2 $3,414.0 $12,867.2 $7,652.9 $2,797.5 $10,450.4 23%Libtayo(c) $659.4 $367.4 $1,026.8 $536.1 $313.8 $849.9 21%Praluent(d) $190.3 $440.7 $631.0 $179.0 $405.6 $584.6 8%Kevzara(b) $271.4 $151.2 $422.6 $187.8 $136.1 $323.9 30%Other products(e) $117.1 $81.5 $198.6 $124.4 $65.2 $189.6 5% 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.(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(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) Included in this line item are products which are sold by the Company and others. Refer to "Third Quarter 2025 Financial Results" section above for a 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.