Alirocumab

Investigational REGN7508 (catalytic domain) and REGN9933 (A2 domain) are being evaluated for their potential to control thrombosis while minimizing bleeding risk in a variety of patient populations and clinical settings Evaluated against current standards of care, single doses of REGN7508 and REGN9933 administered 12 to 24 hours after total knee replacement demonstrated robust antithrombotic effects Phase 3 program to be initiated in 2025 TARRYTOWN, N.Y., Dec. 19, 2024 (GLOBE NEWSWIRE) -- Regeneron Pharmaceuticals, Inc. (NASDAQ: REGN) today announced positive Phase 2 results for two novel monoclonal antibodies targeting distinct domains of Factor XI. REGN7508 (catalytic domain) is designed to maximize anticoagulant activity while minimizing bleeding risk, and REGN9933 (A2 domain) is designed to provide an additional option for patients with the highest bleeding risk who would otherwise not be candidates for currently available anticoagulants. Per the Phase 2 results, there was a robust antithrombotic effect for each antibody, and no clinically relevant bleeding was observed in any treatment arm. “Our Factor XI antibodies targeting the catalytic and A2 domains were rigorously evaluated alongside current standards of care and showed clear evidence of antithrombotic effect with an encouraging safety profile after a convenient single dose,” said George D. Yancopoulos, M.D., Ph.D., Board Co-Chair, President and Chief Scientific Officer at Regeneron. “These latest Phase 2 results add to our preclinical data that showed prolongation of activated partial thromboplastin clotting time was greater with REGN7508 and similar with REGN9933, compared to other Factor XI-targeted agents. Together, these clinical and preclinical data, along with compelling genetic evidence, give us confidence in targeting multiple distinct domains of Factor XI to potentially offer tailored therapies for patients with different bleeding risk profiles and in a variety of treatment settings. We are eager to advance REGN7508 and REGN9933 into a broad Phase 3 program beginning in 2025.” Regeneron conducted two open-label, active-controlled Phase 2 trials (ROXI-VTE-I and ROXI-VTE-II) in the same centers under similar protocols to evaluate REGN7508 and REGN9933 for the prevention of asymptomatic (detected by venogram between day 8 and 12) or symptomatic venous thromboembolism (VTE) after unilateral total knee arthroplasty. In ROXI-VTE-I, patients were randomized to receive either a single intravenous (IV) dose of REGN9933, daily enoxaparin, or twice daily doses of apixaban until the time of venography. In ROXI-VTE-II, patients were randomized to receive a single IV dose of REGN7508 or daily enoxaparin until the time of venography. In contrast to trials evaluating other Factor XI antibodies, administration of all treatments began 12 to 24 hours after surgery (generally one day post-operation) in both trials, consistent with the approved administration of the active comparators. On the measure of VTE rates at venogram following surgery, a pooled analysis across both trials showed REGN7508 was superior to enoxaparin and non-inferior to apixaban, and REGN9933 was non-inferior to enoxaparin. All VTE events were asymptomatic, except for one symptomatic case of pulmonary embolism in the apixaban arm. Results were as follows: REGN7508REGN9933enoxaparinapixaban Historical control (placebo)1Patients with VTE events7%(8 of 113patients)17%(20 of 116patients)21%(36 of 175patients)12%(14 of 113patients) 48%(43 of 89 patients)Difference in VTE incidence (95% confidence interval)REGN7508 vs enoxaparin: -14% (-21% to -6%)* REGN7508 vs apixaban: -5% (-13% to 2%)^REGN9933 vs enoxaparin: -3% (-13% to 6%)^ * Superiority met^ Non-inferiority met with a margin of 9% There was no major bleeding (including surgical site bleeding) or clinically relevant non-major bleeding in any arm; the only treatment-related adverse events (AE) in any arm was one case of minimal bleeding (contusion) reported in the enoxaparin arm of ROXI-VTE-I. There were no treatment-related serious AEs (SAEs) in any arm. There were also no AEs in any arm leading to trial discontinuation or dose interruption/modification, and no AEs of special interest or deaths in these trials. Across both trials, AE rates were generally similar among the treatment arms (ROXI-VTE-I: REGN9933=22%, enoxaparin=21%, apixaban: 25%; ROXI-VTE-II: REGN7508=22%, enoxaparin: 25%). The safety and efficacy of REGN7508 and REGN9933 have not been evaluated by any regulatory authority. About ThrombosisThrombosis, otherwise known as clot formation, is responsible for one in four deaths worldwide. Due to bleeding concerns, current standard-of-care anticoagulants are underutilized and current oral agents are often associated with poor adherence. There is an unmet need for treatments that can help prevent thrombosis without increased bleeding risk. About Regeneron's VelocImmune® TechnologyRegeneron's VelocImmune technology utilizes a proprietary genetically engineered mouse platform endowed with a genetically humanized immune system to produce optimized fully human antibodies. When Regeneron's co-Founder, President and Chief Scientific Officer George D. Yancopoulos was a graduate student with his mentor Frederick W. Alt in 1985, they were the first to envision making such a genetically humanized mouse, and Regeneron has spent decades inventing and developing VelocImmune and related VelociSuite® technologies. Dr. Yancopoulos and his team have used VelocImmune technology to create a substantial proportion of all original, FDA-approved fully human monoclonal antibodies. This includes Dupixent® (dupilumab), Libtayo® (cemiplimab-rwlc), Praluent® (alirocumab), Kevzara®, Evkeeza® (evinacumab-dgnb), Inmazeb® (atoltivimab, maftivimab and odesivimab-ebgn) and Veopoz® (pozelimab-bbfg). In addition, REGEN-COV® (casirivimab and imdevimab) had been authorized by the FDA during the COVID-19 pandemic until 2024. About RegeneronRegeneron (NASDAQ: REGN) is a leading biotechnology company that invents, develops and commercializes life-transforming medicines for people with serious diseases. Founded and led for over 35 years by physician-scientists, our unique ability to repeatedly and consistently translate science into medicine has led to numerous FDA-approved treatments and product candidates in development, almost all of which were homegrown in our laboratories. Our medicines and pipeline are designed to help patients with eye diseases, allergic and inflammatory diseases, cancer, cardiovascular and metabolic diseases, hematologic conditions, infectious diseases and rare diseases. Regeneron is accelerating and improving the traditional drug development process through our proprietary VelociSuite® technologies, such as VelocImmune, which uses unique genetically humanized mice to produce optimized fully human antibodies and bispecific antibodies, and through ambitious research initiatives such as the Regeneron Genetics Center®, which is conducting one of the largest genetics sequencing efforts in the world. For more information, please visit www.Regeneron.com or follow Regeneron on LinkedIn. 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 REGN7508 and REGN9933, two novel monoclonal antibodies targeting distinct domains of Factor XI (together, the “Factor XI Product Candidates”); 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), including the studies discussed or referenced in this press release, on any of the foregoing or any potential regulatory approval of Regeneron’s Products and Regeneron’s Product Candidates (such as any of the Factor XI Product Candidates); the likelihood, timing, and scope of possible regulatory approval and commercial launch of Regeneron’s Product Candidates and new indications for Regeneron’s Products, such as any regulatory approval of any of the Factor XI Product Candidates; the ability of Regeneron’s collaborators, licensees, 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 ability of Regeneron to manage supply chains for multiple products and product candidates; safety issues resulting from the administration of Regeneron’s Products and Regeneron’s Product Candidates (such as any of the Factor XI 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; 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; ongoing regulatory obligations and oversight impacting Regeneron’s Products, research and clinical programs, and business, including those relating to patient privacy; 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; 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); the extent to which the results from the research and development programs conducted by Regeneron and/or its collaborators or licensees (including the Phase 2 studies evaluating the Factor XI Product Candidates discussed in this press release) may be replicated in other studies and/or lead to advancement of product candidates to clinical trials, therapeutic applications, or regulatory approval; 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; the potential for any license, collaboration, or supply 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® (aflibercept) Injection), 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 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). Contacts:RegeneronMedia RelationsMary HeatherTel: +1 914-847-8650mary.heather@regeneron.comInvestor RelationsMark HudsonTel: +1 914-847-3482mark.hudson@regeneron.com 1 Fuji T, Fujita S, Tachibana S, Kawai Y. A dose-ranging study evaluating the oral factor Xa inhibitor edoxaban for the prevention of venous thromboembolism in patients undergoing total knee arthroplasty. J Thromb Haemost. 2010 Nov;8(11):2458-68. doi: 10.1111/j.1538-7836.2010.04021.x. PMID: 20723033.

恒瑞医药在降脂领域再下一城。 继PCSK9抑制剂瑞卡西单抗后，恒瑞另一款降脂新药也取得突破性进展：SHR-1918的首个III期研究启动，评估对纯合家族性高胆固醇血症（HoFH）患者的低密度脂蛋白胆固醇（LDL-C）的降低作用，成为目前国内首个且唯一一个进入III期临床的ANGPTL3单抗。 从PCSK9到ANGPTL3，恒瑞的降脂管线覆盖了极具潜力的新兴靶点，拿下降脂领域新高地的野心展露无疑。 01 恒瑞医药的野心 恒瑞医药之所以野心满满，源于我国降脂领域存在较大未被满足需求。 一方面，降脂领域患者基数大且持续增长，血脂异常多发于60岁以上的老年人群，并呈现患病年轻化趋势，根据国家心血管病中心统计显示，我国血脂异常患病率高达40.4%，人数超过4亿； 另一方面，我国目前降脂治疗率低，传统的他汀类药物存在一定的局限性，虽然新型降脂药PCSK9抑制剂在降脂效果和安全性上表现出色，但其注射剂型不如口服的他汀类药物使用方便，且用药成本较高，这在一定程度上限制了其临床使用。 在巨大的市场需求驱动之下，我国降脂药市场规模从2017年的274.4亿元上升至2022年的470亿元，年复合增长率11.36%，2023年市场规模已经超过500亿元。这无疑是必须拿下的高地。 需求的不断增长，也让一些降脂创新靶点掀起了研发热潮，包括Lp(a)、ANGPTL3、APOC3、CETP等。 其中，ANGPTL3是血管生成素样蛋白家族的成员之一，是肝脏分泌的血清脂质和脂蛋白代谢的关键调节因子，通过抑制内皮脂肪酶（EL）来调节高密度脂蛋白胆固醇（HDL-C）和极低密度脂蛋白胆固醇（VLDL-C）的分解代谢。 恒瑞医药的心血管与代谢管线 图片来源：公司官网 SHR-1918是恒瑞医药自研的ANGPTL3单抗，通过抑制ANGPTL3的活性，从而降低血清中的甘油三酯（TG）和LDL-C水平。 根据恒瑞在2024 ESC年会上公布的I期研究数据显示，SHR-1918能够有效且持久降低LDL-C水平和TG水平：与安慰剂组相比，300mg及以上剂量水平的LDL-C降低超过30%，持续64天以上，最高达9.1%；TG降低超过50%，持续85天以上，最高达82.8%。 今年9月，SHR-1918用于治疗纯合子家族性高胆固醇血症（HoFH）被CDE纳入拟突破性治疗品种公示名单，表明治疗罕见病的潜力得到了认可。 HoFH是一种罕见且严重的遗传性疾病，患者由于低密度脂蛋白胆固醇受体（LDLR）的缺陷或缺失，导致LDL-C在血液中积累，从而增加心脏病和卒中的风险。 目前同靶点药物中，全球只有再生元/Ultragenyx的Evinacumab（Evkeeza，依维苏单抗）于2021年获FDA批准上市，用于治疗HoFH。由于患者数量少且价格高昂，2023年Evkeeza全球销售额约8100万美元，但今年第三季度在美国市场实现3200万美元，同比增长68%。 除了HoFH适应症，恒瑞还针对SHR-1918开展治疗高脂血症患者的II期临床研究。 根据肝胆学顶刊《CUT》最新发布数据，我国高血脂症患者数已超4亿，其中35-60岁人群为重灾区，占比高达86.2%，每年有近400万人死于高血脂并发症，包括但不限于糖尿病、冠心病、脑卒中等。 值得一提的是，恒瑞不止布局了一款降脂药。 02 心血管领域再发力 除了SHR-1918，恒瑞医药在心血管疾病领域还有5款创新药在研，其中有2款针对高脂血症，包括已处于上市审评阶段的SHR-1209（瑞卡西单抗）和HRS-7249。 其中，瑞卡西单抗是全球首个超长效PCSK9单抗，其显著的特点在于能够延长给药间隔（最长可达12周），突破了现有PCSK9单抗给药间隔较短的瓶颈； 非临床药效研究显示，HRS-7249在体内可以发挥高效、持久的降低甘油三脂的作用，具备脱靶风险低，安全性良好的特点，治疗高脂血症已处于I期临床，目前国内外暂无同类产品获批上市。 恒瑞医药心血管疾病管线 图片来源：2024年半年报 不过，PCSK9赛道竞争较为激烈，恒瑞医药面临的挑战不小。 据开源证券研报披露，截至今年9月，国内已有6款PCSK9抑制剂获批上市（其中一款为siRNA药物），处于临床阶段的管线还有22条，其中有8条处于临床II期和III期。 从销售层面看，2020-2023年，受益于纳入医保目录、年治疗费用得到大幅优化，安进/安斯泰来的依洛尤单抗销售额从1.3亿元增长至13.23亿元，CAGR达116.5%，同期再生元/赛诺菲的阿利西尤单抗从0.17亿元增至6.29亿元，CAGR高达235%。 诺华靶向PCSK9的小干扰核酸（siRNA）疗法Leqvio（Inclisiran，英克司兰钠），全球放量速度更为迅猛，得益于“一年仅需注射两次”的长效给药优势，全球销售额从2021年的0.12亿美元飙升至2023年的3.55亿美元，CAGR超过400%，今年前三季度更是达到5.31亿美元，同比增长130%。 在中国市场方面，根据诺华Q1季报电话会议，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。 就看布局了PCSK9抑制剂的国产玩家，包括信达生物、君实生物、信立泰等，能否撼动诺华在降脂药领域的地位了。 靶向PCSK9的长效siRNA制剂展现出巨大商业价值，吸引了不少国内药企争相布局，包括石药集团SYH2053、君实生物RP910、瑞博生物/齐鲁制药RBD7022、悦康药业YKYY015等，但大多仍处于临床I期阶段。 相较之下，恒瑞医药SHR-1918所在的ANGPTL3靶向药物赛道，还是一片亟待开发的蓝海市场，国内药企鲜有布局。 单抗技术路线方面，全球仅再生元/Ultragenyx的依维苏单抗获批；全球尚无同靶点siRNA类药物获批上市。 目前，已处于临床阶段的海外管线，包括Arrowhead的siRNA药物Zodasiran（ARO-ANG3）、礼来的Solbinsiran（LY-3561774）和LY-3475766（靶向ANGPTL3/8复合物）、诺华的LNA043（治疗膝骨关节炎）、辉瑞和Ionis联合开发的反义寡核苷酸（ASO）Vupanorsen等，其中不乏MNC巨头。 另外，舶望制药正在开展siRNA药物BW-01针对重度高甘油三酯血症的II期试验，君实生物研发的siRNA药物JS401正在开展治疗高脂血症的I期临床。 03 结语 近期，恒瑞医药宣布赴港上市的消息引起了业内广泛关注，其剑指海外市场的野心同样展露无疑。 从2023年斩获5笔对外授权合作，到今年以NewCo模式达成60亿美元出海，国际化已经占据了恒瑞医药的重要地位。 正如恒瑞医药副总经理张连山此前在接受媒体采访时表示，“海外战略上我们有所调整，任何一个产品，在任何临床阶段，都会寻求跟海外合作开发。” 参考资料 1.各家公司的财报、公告、官微 2.《医药生物行业降脂药专题：庞大患者群体，关注前沿靶点-241208》，华福证券 3.开源证券研报