mRNA-4157

As a wave of individualized cancer vaccines advances, the FDA's vaccine czar Peter Marks, M.D., Ph.D., is weighing new regulatory questions surrounding the products. As new cancer vaccines—led by Moderna and Merck’s mRNA-4157—near pivotal trial readouts, the FDA’s vaccines czar Peter Marks, M.D., Ph.D., said the agency is ready to review the shots despite AI-related unknowns. “We are ready to review—we’re open for business,” Marks, director of the FDA’s Center for Biologics Evaluation and Research, said of cancer vaccines at the 2024 World Vaccine Congress (WVC). “We have therapeutic cancer vaccines coming in; I think we would review them very much like we could review potentially a CAR-T cell or other therapeutic products,” Marks said. The FDA has approved a cancer vaccine before, namely Dendreon’s prostate cancer shot Provenge. Although the next wave of therapeutic cancer vaccines aim to prove efficacy through familiar clinical endpoints—such as tumor progression and overall survival—the novelty of their tech raises new regulatory questions. And neither the FDA nor the biopharma industry seem to have the full set of answers right now. For the production of CAR-T therapies and Provenge, a patient’s own immune cells are collected and then manipulated to recognize cancer cells. In both cases, although the final products differ based on the patient’s cells, the starting components and the processing steps are the same in nature. For Moderna and Merck’s mRNA candidate mRNA-4157, though, AI dictates how the individualized vaccine should be formulated to attack cancer. The platform sequences a patient’s tumor and healthy tissue and then uses AI to capture the most relevant tumor-specific mutational signatures. Neoantigens identified this way form the basis of the vaccine construct, and the resulting proteins can be very different between individuals. The goal is to induce an immune response against tumors bearing those biomarkers. As AI is a core component of the program, Moderna expects the FDA will need to inspect its algorithm as part of the review of vaccines like mRNA-4157, also known as V940, Kyle Holen, Moderna’s head of development of therapeutics and oncology, told Fierce Biotech on the sidelines of WVC. “We have to put our algorithm on a hard drive, put it in armored truck and have it shipped to the FDA,” Holen said. AI algorithms are known to evolve as they absorb new information. But to protect the integrity of a clinical trial for an AI-based vaccine, Moderna had to “lock down” the algorithm before the study to avoid any changes that may have confounded the results, Holen added. All of this raises a new regulatory question: How much change to the AI algorithm is allowed before the vaccine should be considered a completely new product? “We don’t know,” Holen said. “Nobody knows. We’re in, like, no-man’s land here, because no one’s ever done this.” Moderna has started these discussions internally, but the company doesn’t yet have a conclusion, he added. “I think when the phase 3 trial is complete, you should understand all the data that we generated and use that to train the model and to create a new model,” Holen said during a panel discussion at WVC. “But ultimately what that’s going to result in is the requirement for another randomized trial of the new model versus the old model.” Moderna has talked to the FDA and learned that changing the vendor for genome sequencing and the range in the number of antigens would be considered major changes to the program, Holen said. But it's unclear whether those adjustments would require a supplemental application or a brand-new product filing if they came after an initial approval, he said. “It’s an unexplored space in drug development, when you have the ability to change your drug and how it works and how you manufacture your drug continuously,” Holen said. FDA’s Marks appears to have a more stringent criterion for considering updates to cancer vaccines as new products. “I think the assumption is that most things are going to be new products unless they actually are similar enough to an old one that you can consider for a vaccine, that it’s like a strain change,” Marks told Fierce Biotech. It would be hard to imagine requiring completely new reviews or large randomized clinical trials for every update to a cancer vaccine. That’s why Marks believes the FDA’s yet-to-be-formalized platform technology designation could be helpful. The FDA recently issued draft guidance on the “advanced manufacturing technology” designation program, which was developed as part of the Food and Drug Omnibus Reform Act of 2022. The initiative is viewed as a step to facilitate the development of products based on novel technologies to improve the drug production process. The agency is still separately working on the specifics of the “platform” designation. The idea would be that products developed with the same platform technologies may enjoy streamlined reviews for subsequent advances. The FDA has had the “platform” idea for some time. But it hasn’t really applied the idea to the fullest extent possible, Marks said. “I think the mRNA platforms are going to force us to really try to lean into that," Marks added.

▎药明康德内容团队编辑Gritstone bio今日宣布了其在研个体化癌症疫苗GRANITE与免疫检查点抑制剂及氟嘧啶/贝伐珠单抗联用，作为一线维持治疗转移性微卫星稳定性结直肠癌（MSS-CRC）患者的临床2/3期试验中2期部分的最新积极成果。MSS-CRC患者占了总结直肠癌患者的80-85%，这些患者的肿瘤被认为是“冷”肿瘤，通常对免疫疗法不产生应答。这项随机对照、开放标签研究共有104位患者入组，以1：1的比例随机分配接受GRANITE联合疗法或仅接受氟嘧啶/贝伐珠单抗治疗，这次所公布数据包含67位患者的分析结果。分析显示，无进展生存期（PFS）数据显示GRANITE组患者获益的早期趋势（HR=0.82，95% CI：0.34-1.67），以及高危患者的PFS延长获益（HR=0.52，95% CI：0.15-1.38），这些患者的疾病进展发生得更快。患者接受治疗几个月后所进行循环肿瘤DNA（ctDNA）的分析显示，患者的ctDNA水平与疾病进展之间的关系符合预期，并有利于GRANITE联合疗法组。▲GRANITE临床2/3期试验设计（图片来源：Gritstone bio公司官网）GRANITE联合疗法显示良好的总体耐受性，不良事件为可控；没有患者因不良事件而停止使用GRANITE治疗。Gritstone bio预计2024年第三季度获得成熟的PFS数据，并预计于2025年上半年获得总生存期数据。图片来源：123RFGRANITE是一种基于肿瘤新抗原的mRNA疫苗。这款癌症疫苗的设计首先从患者体内获取活检组织，对肿瘤进行测序，然后利用专有人工智能平台EDGE筛选出肿瘤特异性新抗原。这种癌症疫苗需要接种两次，第一次利用腺病毒载体递送表达新抗原的基因，第二次使用自我扩增mRNA（self-amplifying mRNA）载体递送表达新抗原的mRNA，进而引发显著的T细胞反应，特别是CD8+细胞毒性T细胞。GRANITE已获得美国FDA的快速通道资格，用于治疗MSS-CRC患者。大家都在看药明康德为全球生物医药行业提供一体化、端到端的新药研发和生产服务，服务范围涵盖化学药研发和生产、生物学研究、临床前测试和临床试验研发、细胞及基因疗法研发、测试和生产等领域。如您有相关业务需求，欢迎点击下方图片填写具体信息。▲如您有任何业务需求，请长按扫描上方二维码，或点击文末“阅读原文/Read more”，即可访问业务对接平台，填写业务需求信息▲欲了解更多前沿技术在生物医药产业中的应用，请长按扫描上方二维码，即可访问“药明直播间”，观看相关话题的直播讨论与精彩回放参考资料：[1] Gritstone bio Announces Positive Preliminary Progression-free Survival and Long-term Circulating Tumor DNA (ctDNA) Data from Phase 2 Portion of Ongoing Phase 2/3 Study of its Personalized Cancer Vaccine, GRANITE, in Front-line Metastatic Microsatellite Stable Colorectal Cancer (MSS-CRC). Retrieved April 1, 2024 from https://www.globenewswire.com/news-release/2024/04/01/2855416/0/en/Gritstone-bio-Announces-Positive-Preliminary-Progression-free-Survival-and-Long-term-Circulating-Tumor-DNA-ctDNA-Data-from-Phase-2-Portion-of-Ongoing-Phase-2-3-Study-of-its-Persona.html免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。版权说明：本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。分享，点赞，在看，聚焦全球生物医药健康创新