Nirsevimab

一代“药王”修美乐®逐步离开舞台中央，免疫领域的制药巨头排位赛进入洗牌阶段，谁会是艾伯维的强劲敌手？其中答案必有赛诺菲。不断创造里程碑的达必妥®（度普利尤单抗）是赛诺菲在免疫领域冲锋的底气。特应性皮炎、哮喘、结节性痒疹（PN）等皮肤疾病和呼吸疾病均留下了达必妥®革新治疗范式的足迹。今年7月，达必妥®凭借优异的疗效再次解锁新地图，成为了慢性阻塞性肺疾病（简称慢阻肺病，COPD）领域首款获批的生物制剂。9月27日，达必妥®在中国顺利获批慢阻肺病适应症，中国慢阻肺病靶向治疗困局终于迎来破局者。在近期举办的欧洲呼吸学会（ERS）年会上，赛诺菲也公开了达必妥®的两项慢阻肺病III期研究汇总分析数据，进一步展示了达必妥®在慢阻肺病上的卓越疗效，为其引领慢阻肺病治疗变革提供了更多有力的证据。BOREAS和NOTUS研究的汇总分析数据[1]达必妥®的成功秘籍是赛诺菲对2型炎症通路的深刻理解，因此其从未停下扩展适应症的步伐。作为开路先锋的达必妥®为赛诺菲渗透免疫领域之路踩好了点，而其后备军正在迎头赶上，赛诺菲进击免疫领域“头号玩家”的旅程已来到下一阶段。悟透2型炎症通路，达必妥®搅动免疫江湖由IL-4、IL-5和IL-13等2型细胞因子介导的2型免疫应答是维持机体内稳态的重要关卡，这个过程的失衡会导致一系列2型炎症性疾病的发生。在这个过程中，2型细胞因子就像一个串联前后的开关，既是炎症性细胞军团出征的号角也是细胞因子工厂运转的动力。达必妥®作为一款拮抗IL-4/IL-13与IL-4Rα结合的单抗，便是以此压制2型炎症反应的强度，从而控制炎症性疾病的发生发展。在2型炎症的治疗上，达必妥®积累了大量的临床证据。经过十来年的探索，达必妥®已在特应性皮炎、哮喘、慢性鼻窦炎伴鼻息肉（CRSwNP）、结节性痒疹（PN）、嗜酸性细胞性食管炎（EoE）、慢性自发性荨麻疹（CSU）和慢阻肺病等多个炎症性疾病上充分展示了其治疗潜力。随着炎症地图的接连解锁，达必妥®的全球年销售额一路走高，已成长为超级“重磅炸弹”。2017-2023年达必妥®全球销售额但达必妥®在2型炎症性疾病上的潜力远不止于此。赛诺菲仍然在深度挖掘达必妥®对其它2型炎症性疾病的应用潜力，例如大疱性类天疱疮（BP）、慢性特发性荨麻疹（CIU）、过敏性支气管肺曲霉病（ABPA）等。近期，达必妥®针对BP和CSU的两项III期研究双双达到主要终点，有望创造新的里程碑。常见2型炎症性疾病及相关证据和治疗靶点[2]赛诺菲深谙2型免疫应答的奥秘，将可阻断关键核心驱动因子IL-4/IL-13响应的达必妥®打造为抵抗2型炎症的利器。这样的独特机制有别于修美乐®（阿达木单抗）、喜达诺®（乌司奴单抗）、可善挺®（司库奇尤单抗）等已上市免疫产品，而这一特点也决定了达必妥®独特的扩张路线——以2型炎症性疾病为中心向外渗透。达必妥®先行破局，后招蓄势待发达必妥®是赛诺菲进军免疫领域的先行棋，而其后备军已准备加入战场。以慢阻肺病为例，赛诺菲在这一疾病领域做了全面的准备。在达必妥®出现之前，以吸入支气管舒张剂和抗炎药物为主的传统治疗方式虽然可改善慢阻肺病患者的疾病症状、减缓疾病进程，但仍有部分患者容易面临难以预防急性加重、局部免疫功能低下、未来感染风险增加等问题，甚至在接受三联疗法后仍会出现中度或重度急性加重的情况。相当于慢阻肺病患者只能通过“对症治疗”缓解疾病症状，但对疾病反复恶化加重带来的“死亡螺旋”威胁仍任重道远。严峻的疾病形势让慢阻肺病成为了全球防治的共同目标。中国是慢阻肺病大国，我国慢阻肺病总患病人数约1亿[3]，国家卫健委已在“健康中国2030”行动计划中将其列为重点防治疾病，慢阻肺病患者健康服务也在近期被纳入了国家基本公共卫生服务项目。近期，慢阻肺病治疗破局迎来了曙光。达必妥®于今年7月在欧盟获批慢阻肺病适应症，为慢阻肺病的治疗手段革新迈出靶向治疗的第一步。有研究发现，除了IL-4/IL-13以外，IL-33/IL-33R通路亦深度参与慢阻肺病的发病进程。IL-33属于IL-1家族，在2型炎症[4]和非2型炎症[5]中均扮演着重要角色，而最终哪种炎症反应占上游与患者的吸烟状况有关。从2型炎症通路来看，IL-33与IL-33R（别称ST2L）结合后，募集IL-1受体附属蛋白（IL-1RAcP），而后便可通过级联反应激活下游炎症细胞因子的分泌，包括促进2型细胞分泌IL-4和IL-13[6,7]。而IL-33/IL-33R介导的非2型炎症通路则主要诱导肿瘤坏死因子-α（TNF-α）和干扰素-γ（IFN-γ）等细胞因子的分泌[8]。IL-33/IL-33R通路[9]IL-33/IL-33R对2型炎症和非2型炎症通路的双调控作用为慢阻肺病的治疗找到了新的突破点。赛诺菲的策略是双管齐下，即开发针对IL-33/IL-33R通路的靶向药物，将其与达必妥®形成组合拳，预计以此覆盖80%的慢阻肺病患者。来源：赛诺菲2023年研发日PPT目前的IL-33/IL-33R疗法以抑制2型炎症为主。据医药魔方Nextpharma数据库统计，全球进入临床阶段的IL-33/IL-33R药物屈指可数，而赛诺菲的IL-33单抗Itepekimab处于第一梯队。Itepekimab在慢阻肺病上的疗效已初步显露。在II期研究中，Itepekimab可将已戒烟慢阻肺病患者的急性加重发生率降低42%（P=0.0061）[10]。赛诺菲已在Itepekimab的两项III期研究中将已戒烟人群列为重点，这两项研究将在2025年揭晓结果。赛诺菲有望在慢阻肺病领域再次带来突破。来源：赛诺菲2023年研发日PPT多样化产品矩阵，赛诺菲免疫拼图完善进行时借助达必妥®，赛诺菲深挖2型炎症通路的临床价值和商业价值。另一方面，赛诺菲正在打造“超越2型炎症”的产品管线，通过多样化的产品矩阵覆盖呼吸疾病的预防和治疗，并在炎症性疾病领域创造更多可能性。在威胁婴幼儿健康的呼吸道合胞病毒（RSV）感染领域，赛诺菲也达成了里程碑成就，推出了第一款可用于婴儿的RSV单抗乐唯初®（尼塞韦单抗）。该产品已在去年年底正式登陆中国。赛诺菲还开发了RSV鼻喷疫苗SP0125，希望为全年龄段婴幼儿进一步提供保护。乐唯初与SP0125可在第一个流行季（当年10月-次年3月）和第二个流行季（次年4月-次年9月）为所有婴幼儿群体提供全面保护。赛诺菲预计最早将在2026年提交该疫苗的上市申请。来源：赛诺菲2023年疫苗研发日PPT赛诺菲正在打造另一款可以像达必妥®一样横跨皮肤科和呼吸科的产品，即靶向阻断共刺激受体OX40的配体OX40L的全人源化单抗Amlitelimab。OX40L/OX40信号轴参与2型炎症和非2型炎症的病理生理发生，也是炎症性疾病的理想治疗靶点。全球临床在研药物以OX40单抗为主，而Amlitelimab是进度领先的靶向OX40L的单抗。相比于靶向OX40的单抗，Amlitelimab的不耗竭T细胞，恢复免疫稳态。来源：赛诺菲2023年研发日PPT特应性皮炎是Amlitelimab的首发适应症，其安全性和疗效已在II期研究中得到初步验证。基于II期研究数据，赛诺菲已启动5项在中国同步开展的全球多中心III期临床探索Amlitelimab对特应性皮炎的有效性和安全性。此外，赛诺菲也在哮喘患者中启动了Amlitelimab的II期研究[11]。来源：赛诺菲2023年研发日PPT与OX40共表达于激活的T细胞表面的CD40L也是赛诺菲看中的免疫性疾病靶点。CD40/CD40L是触发机体的适应性免疫应答和先天性免疫应答过程的关键介质，其过度激活会导致自身免疫性疾病的发生。赛诺菲基于此开发的Frexalimab是全球进度领先的CD40L单抗。来源：赛诺菲2023年研发日PPT赛诺菲为Frexalimab选择的首发适应症是多发性硬化症（MS），其疗效也已在II期研究中初步显现。目前，赛诺菲正在复发性MS和继发进展型MS患者中开展Frexalimab的III期临床。值得注意的是，Frexalimab还具备延缓1型糖尿病进展[12]的潜力，有望与赛诺菲管线中已上市的Tzield®（替利珠单抗）打组合拳，让更多糖尿病患者获益。来源：赛诺菲2023年研发日PPT赛诺菲对Amlitelimab和Frexalimab寄予厚望，预计两款药物的峰值销售额均可达到50亿欧元。在赛诺菲的管线中还有一款药物同样被其放在高市场潜力队列中——口服肿瘤坏死因子受体1（TNFR1）抑制剂SAR441566。修美乐虽迟暮，但TNF领域的竞赛还未落幕，TNF-α抗体逐渐退场之时，口服TNF产品已入场。来源：赛诺菲2023年研发日PPTSAR441566是目前进度最快的小分子TNFR1抑制剂，其优势在于可以选择性阻断TNFR1，避免了TNF-α抗体同时阻断TNFR2带来的负面影响，且其口服剂型避免了生物制剂产生抗药抗体而可能降低疗效的问题。目前，SAR441566已完成一项针对斑块状银屑病患者的Ib期研究。结果显示，相比于安慰剂组，SAR441566组患者的银屑病面积和严重程度指数（PASI）在治疗4周时改善更显著（35.09% vs. 15.71%，P=0.009）[13]。来源：赛诺菲2023年研发日PPT在推进管线产品开发的同时，赛诺菲也从BD上着手加强其免疫管线布局，例如引进梯瓦（Teva）的TL1A单抗duvakitug、收回Rezurock®（贝舒地尔）的中国权益。总结赛诺菲并非免疫赛道的“老牌”玩家，但在达必妥®的加持之下势如破竹，去年已跻身自免巨头TOP3[14]。今年，随着达必妥®达到新的里程碑以及自免巨头的洗牌，赛诺菲在免疫领域的进击之旅也来到了新的起点。赛诺菲在免疫领域的影响力有目共睹，而通过多维度纵深布局的免疫管线，赛诺菲正在加速成为免疫领域的领导者。推荐阅读走出COPD新药研发“死亡谷”：赛诺菲解锁炎症性疾病新“地图”版图扩张，赛诺菲进击“免疫巨头”王座- 上下滑动查看参考资料 - [1] 医学界呼吸频道.2024.9《直击ERS，优享前沿 | 伴2型炎症的慢性阻塞性肺疾病研究进展》[2] 中华医学会变态反应学分会.2型炎症性疾病机制及靶向治疗专家共识[J].中华医学杂志, 2022, 102(42):25.DOI:10.3760/cma.j.cn112137-20220628-01431.[3]Wang C, et al. Lancet 2018;391(10131):1706-17.[4]Liew FY, Girard JP, Turnquist HR. Interleukin-33 in health and disease. Nat Rev Immunol. 2016 Nov;16(11):676-689. doi: 10.1038/nri.2016.95. Epub 2016 Sep 19. PMID: 27640624.[5]Calderon AA, Dimond C, Choy DF, Pappu R, Grimbaldeston MA, Mohan D, Chung KF. Targeting interleukin-33 and thymic stromal lymphopoietin pathways for novel pulmonary therapeutics in asthma and COPD. Eur Respir Rev. 2023 Jan 25;32(167):220144. doi: 10.1183/16000617.0144-2022. Erratum in: Eur Respir Rev. 2023 Apr 5;32(168):225144. doi: 10.1183/16000617.5144-2022. PMID: 36697211; PMCID: PMC9879340.[6]Schmitz J , Owyang A , Oldham E ,et al.IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines.[J].Immunity, 2005, 23(5):479-490.DOI:10.1016/j.immuni.2005.09.015.[7]Groot J C D , Brinke A T , Bel E H D .Management of the patient with eosinophilic asthma: a new era begins[J].ERJ Open Research, 2015, 1(1):00024-2015-24-2015.DOI:10.1183/23120541.00024-2015.[8]Zhou Z , Yan F , Liu O .Interleukin (IL)‐33: an orchestrator of immunity from host defence to tissue homeostasis[J].Wiley-Blackwell Online Open, 9(6)[2024-09-20].DOI:10.1002/cti2.1146.[9] Zhou Y , Xu Z , Liu Z .Role of IL-33-ST2 pathway in regulating inflammation: current evidence and future perspectives[J].Journal of Translational Medicine, 2023, 21(1).DOI:10.1186/s12967-023-04782-4.[10] BPKFRA , CPBRC , DPMEW ,et al.Safety and efficacy of itepekimab in patients with moderate-to-severe COPD: a genetic association study and randomised, double-blind, phase 2a trial[J].The Lancet. Respiratory medicine, 2021, 9(11):1288-1298.DOI:10.1016/S2213-2600(21)00167-3.[11] Study Details | Long-term Safety and Efficacy Evaluation of Subcutaneous Amlitelimab in Adult Participants With Moderate-to-severe Asthma Who Completed Treatment Period of Previous Amlitelimab Asthma Clinical Study | ClinicalTrials.gov[12] Mahmoud T I , Wang J , Karnell J L ,et al.Autoimmune manifestations in aged mice arise from early-life immune dysregulation[J].Science Translational Medicine, 2016, 8(361):361ra137.DOI:10.1126/scitranslmed.aag0367.[13] The Potential of an Oral TNF-α Inhibitor with TNFR1 Specificity: Results of a Phase 1b Proof-of-mechanism Trial in Psoriasis.[14] 医药魔方.2024.2《2023年全球制药巨头自免业务排名TOP10》Copyright © 2024 PHARMCUBE. All Rights Reserved.欢迎转发分享及合理引用，引用时请在显要位置标明文章来源；如需转载，请给微信公众号后台留言或发送消息，并注明公众号名称及ID。免责申明：本微信文章中的信息仅供一般参考之用，不可直接作为决策内容，医药魔方不对任何主体因使用本文内容而导致的任何损失承担责任。

AstraZeneca on Tuesday lifted its earnings outlook for the full year, boosted by strong sales growth across its portfolio. However, investor and analyst attention will be firmly focused on the company's performance in China amid ongoing investigations into the conduct of one of its executives.Leon Wang, head of the pharma's operations in China, is said to be cooperating with a probe by authorities in the country, although details are scarce. The investigation reportedly comes after Chinese police recently detained five current and former AstraZeneca employees over allegations of medical insurance fraud, illegal drug importation and personal information breaches. On Tuesday, AstraZeneca CEO Pascal Soriot said "we take the matters in China very seriously. If requested we will fully cooperate with the authorities."With China looming large, US get investmentAstraZeneca said Tuesday it will invest $3.5 billion on expanding its research and manufacturing footprint in the US by the end of 2026. The figure includes $2 billion of new investment that will create over 1000 jobs, with Soriot noting that the move "reflects the attractiveness of the business environment" in the country.The US continues to represent AstraZeneca's largest market, with third-quarter revenue in the country rising 23% to $6 billion — twice the value of European sales, which were up 22% to $2.9 billion — while growth in China was 15% to $1.7 billion. The company's overall sales in the quarter jumped 18% to $13.6 billion, driven by products including Tagrisso (+14%, $1.7 billion), Enhertu (+50%, $510 million) and Beyfortus (+73%, $238 million). Profit in the three-month period grew 4% to $1.4 billion.For the full year, AstraZeneca expects both sales and core earrings per share to increase by a high teens percentage, up from a prior estimate of a mid teens percentage rise.Dato-DXd change of tack AstraZeneca and partner Daiichi Sankyo have withdrawn a US filing seeking approval of the TROP2-directed antibody-drug conjugate datopotamab deruxtecan (dato-DXd) for patients with advanced or metastatic non-squamous non–small-cell lung cancer (NSCLC). The companies have instead submitted a new application for the treatment of adults with locally advanced or metastatic EGFR NSCLC who have received prior systemic therapies, including an EGFR-directed therapy.The initial filing was based on the Phase III TROPION-Lung01 trial, while the new submission includes data from the study, but is mainly based on the mid-stage TROPION-Lung05 trial. New results from a pooled analysis of patients with previously treated EGFR-mutated NSCLC in the two studies trials will be featured in a late-breaking presentation at the upcoming European Society for Medical Oncology (ESMO) Asia congress."The results…showed an especially pronounced benefit for patients with an EGFR mutation which informed our discussions with the FDA and the decision to seek accelerated approval of datopotamab deruxtecan in this patient population," remarked Susan Galbraith, EVP of oncology R&D at AstraZeneca.Bloomberg Intelligence analyst John Murphy suggested that the move "could drive further cuts to long-term sales estimates for this potential blockbuster drug," while Jefferies' Peter Welford said the withdrawal and re-submission of the FDA application was "a setback but not entirely unanticipated."KOMET rockets to study winThe Phase III KOMET study of Koselugo (selumetinib) in adults with neurofibromatosis type 1 (NF1) who have symptomatic, inoperable plexiform neurofibromas (PN) met its primary endpoint. In the trial, the oral, selective MEK inhibitor demonstrated a statistically significant and clinically meaningful objective response rate (ORR) versus placebo.Koselugo — which is partnered with Merck & Co. — is currently approved for the treatment of certain paediatric patients with NF1 who have symptomatic, inoperable PN. AstraZeneca noted that the top-line KOMET results support expanding use of the drug into adults, with the data set to be shared with regulatory authorities.