mRNA-1073

作为仅有新冠产品上市商业化的药企，Moderna的下滑幅度比想象中还要快。2022年，Moderna全年营收184亿美元，到今年可能仅在50至60亿美元附近徘徊。如此情形下，Moderna曾表示公司将在“必要时”以管线的优先度来精简化资产。于是在近日，Moderna透露将削减目前4项临床管线，其中包括此前与阿斯利康合作开发的两项资产。AZD8601首当其冲的是与阿斯利康合作开发的mRNA 编码血管内皮生长因子A（VEGF-A）的疗法AZD8601。VEGF-A 作为一种旁分泌因子，参与新血管形成，有助于心脏修复和再生的特殊细胞的产生。在2021年年底的一项 2a 期临床试验中，七名患者接受冠状动脉搭桥手术的患者的心肌中被注射了AZD8601，四名接受了安慰剂。对于研究结果，阿斯利康曾表示治疗取得了积极效果，AZD8601达到了安全性和耐受性主要终点。七名接受AZD8601治疗的患者在随访的6个月内，NT-proBNP（一种测量心力衰竭患者激素水平升高的生物标记物）水平均低于心力衰竭限值，而安慰剂组中1名患者高于限值。然而，尽管这些结果是乐观的，但阿斯利康在去年季度更新中，仍然删除了这一已处于2期临床试验阶段的资产。如今Moderna紧随其后也放弃了AZD8601。MEDI1191MEDI1191与AZD8601同样命运多舛，由阿斯利康和Moderna合作开发。MEDI1191是一款可编码免疫激活性细胞因子IL-12的mRNA疗法，通过驱动局部 IL-12 产生并诱导抗肿瘤活性。MEDI1191的早期临床效果不错，在联合Imfinzi治疗晚期实体瘤患者安全性良好，未观察到DLT，无3级以上治疗相关不良事件。但到了2022年，该项目的临床表现却不如人意。根据2022年AACR公开数据，MEDI1191联合PD-L1抑制剂治疗晚期实体瘤的效果不佳，在31例接受联合治疗的患者中，仅有3位患者出现部分缓解、10位患者疾病稳定。于是阿斯利康在去年11月将该项目归还给了Moderna，如今Moderna采取了相同的措施彻底放弃了此药物。mRNA-1653第三款是mRNA-1653，这是一款针对的是人类偏肺病毒（hMPV）和3型副流感病毒（PIV3）。这两种病毒都属于单链RNA病毒，是引起婴幼儿严重呼吸道感染和住院治疗的重要原因，目前都还没有批准的预防性疫苗。mRNA-1653由两段mRNA序列组成，分别编码两种病毒的融合蛋白，由Moderna专有的脂质纳米颗粒（LNP）技术递送。此前公布过1期临床试验的结果，招募了52名患者，单次接种mRNA-1653显著提高血清中和抗体滴度，且四个剂量达到的滴度增幅相当。接种一个月后，hMPV中和抗体滴度与PIV3中和抗体滴度分别约为基线滴度的6倍和3倍。相隔一个月后接种的第二剂并未继续提高血清抗体滴度，说明单次接种足以使抗体水平达到稳定高度。安全性未有不良事件，最常见的症状为注射部位疼痛。尽管mRNA-1653临床试验结果看上去不错，但作为早期项目继续推进将烧掉不少钱。而且，人类偏肺病毒和3型副流感病毒对除婴幼儿的患者外，症状轻微，轻症者完全可自愈，未来商业化回报不高。于是Moderna决定放弃这项资产。mRNA-1073mRNA-1073是新冠疫情期Moderna研发的新冠/流感二联疫苗，属于泛呼吸道疫苗。mRNA-1073包含表达新冠刺突蛋白和4种流感病毒株HA糖蛋白的mRNA，其发挥作用时可引起机体同时编码新冠病毒刺突蛋白和流感病毒的血凝素糖蛋白，触发免疫机制。mRNA-1073的推进非常缓慢。作为新冠疫苗立项3年直到去年曾才入组1050例健康志愿者，参与其1/2期临床研究。但此项临床数据迟迟没有公布披露。随着新冠潮的逐渐褪去，mRNA-1073被剔除出管线也是理所应当的。为重要管线铺平道路9月13日，Moderna公布了其流感疫苗的3期临床研究结果，其基于mRNA技术平台的试验性季节性流感疫苗mRNA-1010对四种流感病毒株产生了比目前市售疫苗更强的免疫反应。当日Moderna股价大涨超过7%。Moderna称其流感疫苗的有效性在包括老年人在内的所有年龄组的受试人群中均得到了证明，并且被证明是安全且可耐受的。Moderna还表示，在一项单独的早期一对一研究中，该公司发现其流感疫苗与赛诺菲(SNY.US)的大剂量流感疫苗效果相同、或优于后者。目前全球范围内尚未有任何一款mRNA流感疫苗获批上市， Moderna对流感疫苗mRNA-1010寄予厚望。除流感疫苗外，Moderna还在推进基于mRNA技术的RSV疫苗，并在此前3期研究中获得积极结果。据分析，RSV疫苗和流感疫苗最快能在明年获批上市，有望弥补今年日益下滑的新冠疫苗收入。参考资料：1.https://www.fiercebiotech.com/biotech/moderna-follows-astrazenecas-lead-dumping-2-previously-shared-programs-plus-2-more本周好文推荐如需转载请联系佰傲谷并在醒目位置注明出处﹀ ···

Pictured: Moderna headquarters in Massachusetts/iStock, hapabapa Moderna on Wednesday announced it was dropping four clinical development programs from its roster, including two molecules that had also been previously culled by AstraZeneca. The decision to discontinue the four clinical programs was part of Moderna’s routine review of its pipeline, in which it evaluates whether there are better opportunities and areas of focus for its mRNA-based drug discovery, design and development platform, President Stephen Hoge said during the company’s annual R&D Day. “We have a blessing and a curse in terms of how productive this platform is, and anytime we see an opportunity to focus our energy on programs that we think are the most important to move forward, we’ll do so,” Hoge said. Moderna’s pipeline cull will affect two formerly AstraZeneca-partnered molecules: the VEGF-A program AZD8601 and the IL-12 program MEDI1191. AZD8601 is an mRNA therapeutic encoding for VEGF-A. In November 2021, Moderna posted data from the AstraZeneca-led Phase II EPICCURE study, which found that injecting the candidate into heart tissue was safe and tolerable, while eliciting signals of efficacy such as improved left ventricular ejection fraction and patient-reported outcomes. AstraZeneca announced it was dropping AZD8601 from its roster in August 2022. A few months later, in November 2022, AstraZeneca also pulled its support from the IL-12 program MEDI1191, which it was studying as part of a combination regimen with the PD-L1 inhibitor durvalumab for the treatment of advanced solid tumors. MEDI1191 is a lipid nanoparticle-formulated candidate that induces the production of IL-12 and promotes anti-tumor activity. In addition to these two candidates, Moderna announced during Wednesday’s R&D Day that it was likewise dropping mRNA-1653, the company’s vaccine candidate for pediatric human metapneumovirus and parainfluenza type 3 virus. The investigational shot was being assessed in a Phase Ib study. Moderna is also abandoning its first-generation COVID-19 and flu combination vaccine mRNA-1073. During its 2022 R&D Day, the company announced that it was assessing the candidate in a Phase I/II trial. Moderna is also advancing a triple-target vaccine, mRNA-1230, which is likewise in a Phase I/II study for COVID-19, flu and respiratory syncytial virus. The news about culling four programs from its pipeline came the same day as the Massachusetts-based biopharma celebrated a Phase III victory for its mRNA-based flu vaccine candidate. Also revealed during Wednesday’s R&D Day, the investigational shot—dubbed mRNA-1010—met all its co-primary endpoints across all four influenza A and B strains, according to an interim analysis of the late-stage study. Tristan Manalac is an independent science writer based in Metro Manila, Philippines. He can be reached at tristan@tristanmanalac.com or tristan.manalac@biospace.com.