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

摘要 自2015年FDA批准FILGRATIM的生物类似物Zarxio®以来，许多大型制药公司已经开始 将生物仿制药产品组合添加到他们的产品线中。截至2022年4月，目前有11种产品的35种生物仿制药 由Sandoz、Amgen、Pfizer等知名公司赞助。成本节约已经在 已实现并将在未来几年继续增长，因为更多的创新者生物制品失去了它们的排他性。生物仿制药 在2020年为美国医疗系统节省了80亿美元，据估计， 到2025年，与生物仿制药相关的节省将达到380亿至1330亿美元[1]，这要归功于这些巨大的节省，随后， 减少患者自付费用，不断扩大的生物相似市场预计将增加患者的准入 这些改变生活的产品[2]。在过去的一年里，我们看到了生物相似领域的进一步进步。 经批准的两种可互换产品--Semglee®(甘精胰岛素)和Cyltezo®(Adalimumab)。 有了这种可互换的状态，Semglee®(甘精胰岛素)和Cyltezo®(Adalimumab)可以自动 药剂师在没有咨询处方的情况下更换了创新者产品。 可以理解，对生物仿制药和/或来自所有利益相关者(即医生， 患者、药剂师、付款人、制药业)是巨大的。由于这种需要，有90多个 据报道，公司的管道内正在开发生物仿制药。鉴于中国生物仿制药的数量 发展，迫切需要健壮、成熟和可获得的方法，使公司能够 在描述生物仿制药的关键属性，如物理化学性质、有效性、 免疫原性、互换性。通过申请BsUFA资助的赠款，我们寻求帮助发展， 可应用于多种生物相似类型的方法的实施和标准化。因此，我们是 建议五个目标是在以下相关领域对多个生物相似/创新者对进行研究 BsUFA：1)结构特征；2)高阶结构；3)聚集及其对稳定性和稳定性的影响 免疫原性；4)糖基化及其对功能的影响；5)技术和监管障碍 可互换的批准。我们实验室在生物相似分析比较方面的广泛背景，除了我们的 与FDA、行业和UM医院系统的成员在几个正在进行的 这一领域的项目使我们成为实现拟议目标的有力候选者，以支持高效的生物相似 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.