Systematic Analytical Characterization of Innovator and Biosimilar Products with the Focus on Post-translational Modifications

摘要 自2015年FDA批准Zarxio®（一种非格司亭的生物仿制药）以来，许多大型制药公司开始 增加了一个生物仿制药组合。截至2022年4月，已有11种产品的35种生物类似药 由知名公司赞助，如山德士，安进，辉瑞等。 随着越来越多的创新生物制剂失去其排他性，这一趋势已经实现，并将在未来几年继续增长。生物药品 到2020年，美国医疗保健系统将节省80亿美元，估计将有 到2025年，生物类似药相关的节省将达到380亿至1330亿美元[1]由于这些巨大的节省， 减少患者的自付费用，扩大生物类似药市场预计将增加患者的可及性 这些改变生活的产品[2]。在过去的一年里，我们看到了生物类似药领域的进一步发展。 批准了两种可互换产品- Semglee®（甘精胰岛素）和Cyltezo®（阿达木单抗）。 通过这种可互换的状态，Semglee®（甘精胰岛素）和Cyltezo®（阿达木单抗）可以自动 药剂师在未咨询处方医生的情况下将药物转换为创新药物。 可以理解的是，所有利益相关者（即医生， 患者、药剂师、付款人、制药行业）是巨大的。由于这种需要，有90多个 据报道，公司正在开发生物仿制药。考虑到生物仿制药的数量， 为了促进发展，迫切需要为公司提供强有力的、既定的和可获得的方法， 在表征生物仿制药的关键属性时实施，如理化性质，功效， 免疫原性、可重复性。通过申请这项BsUFA资助的赠款，我们寻求援助的发展， 可应用于多种生物类似药类型的方法的实施和标准化。因此，我们 提出五项建议的目的是在以下相关领域对多种生物仿制药/创新药对进行研究， BsUFA：1）结构特征; 2）高级结构; 3）聚集及其对稳定性的影响， 免疫原性; 4）糖基化及其对功能性的影响; 5）免疫原性的技术和监管障碍。 可互换的批准。我们实验室在生物类似药分析比较方面的广泛背景，除了我们的 与来自FDA、行业和UM医院系统的成员密切合作， 在这一领域的项目，使我们成为一个强有力的候选人，以执行拟议的目标，以支持有效的生物类似药 发展

ABSTRACT Since the FDA approval of Zarxio®, a biosimilar for filgrastim, in 2015, many big pharma companies have begun adding a biosimilars portfolio to their pipeline. As of April 2022, there are now 35 biosimilars for 11 products sponsored by well-known companies such as Sandoz, Amgen, Pfizer, etc. Cost savings are already being realized and will continue to grow in upcoming years as more innovator biologics lose their exclusivity. Biosimilars resulted in $8B in savings to the US healthcare system in 2020 and it is estimated there will be anywhere from $38B - $133B in biosimilars-related savings come 2025[1] Owing to these large savings and, subsequently, reduced patient out-of-pocket expenses, the expanding biosimilar market is expected to increase patient access to these life-changing products[2]. Within the last year we saw even further advancements in the biosimilar field with the approval of two interchangeable products – Semglee® (insulin glargine) and Cyltezo® (adalimumab). With this interchangeable status, Semglee® (insulin glargine) and Cyltezo® (adalimumab), can be automatically switched for the innovator product by pharmacists without consulting the prescriber. Understandably, the need for biosimilars and/or interchangeable products from all stakeholders (i.e. physicians, patients, pharmacists, payers, pharmaceutical industry) is immense. Owing to this need, there are over 90 reported biosimilars under development within companies' pipelines. Given the number of biosimilars in development, there is an urgent need for robust, established and accessible methodologies for companies to implement when characterizing key attributes of biosimilars such as physicochemical properties, efficacy, immunogenicity, interchangeability. By applying for this BsUFA funded grant, we seek to aid in the development, implementation and standardization of methods that can be applied to multiple biosimilar types. As such, we are proposing five aims to conduct research on multiple biosimilar/innovator pairs in the following areas relevant to BsUFA: 1) structural features; 2) higher order structure; 3) aggregation and its effect on stability and immunogenicity; 4) glycosylation and its impact on functionality; 5) technical and regulatory hurdles for interchangeable approval. Our lab's extensive background in biosimilar analytical comparisons, in addition to our close collaborations with members from the FDA, industry, and the UM hospital system on several ongoing projects in this area, make us a strong candidate to perform the proposed aims in support of efficient biosimilar development.