Novo Nordisk A/S, Global Research Technologies, Novo Nordisk Park, DK-2760 Maaloev, Denmark.
Novo Nordisk A/S, Global Drug Discovery, Novo Nordisk Park, DK-2760 Maaloev, Denmark.
J Med Chem. 2021 Jan 14;64(1):616-628. doi: 10.1021/acs.jmedchem.0c01576. Epub 2020 Dec 28.
Recently, the first basal oral insulin (OI338) was shown to provide similar treatment outcomes to insulin glargine in a phase 2a clinical trial. Here, we report the engineering of a novel class of basal oral insulin analogues of which OI338, , in this publication, was successfully tested in the phase 2a clinical trial. We found that the introduction of two insulin substitutions, A14E and B25H, was needed to provide increased stability toward proteolysis. Ultralong pharmacokinetic profiles were obtained by attaching an albumin-binding side chain derived from octadecanedioic (C18) or icosanedioic acid (C20) to the lysine in position B29. Crucial for obtaining the ultralong PK profile was also a significant reduction of insulin receptor affinity. Oral bioavailability in dogs indicated that C18-based analogues were superior to C20-based analogues. These studies led to the identification of the two clinical candidates OI338 and OI320 ( and , respectively).
最近，一项 2a 期临床试验表明，首款基础口服胰岛素（OI338）在治疗效果上可与甘精胰岛素相媲美。在此，我们报告了一类新型基础口服胰岛素类似物的工程设计，其中 OI338，在本出版物中，已在 2a 期临床试验中成功测试。我们发现，需要引入两个胰岛素取代基 A14E 和 B25H，以提供对蛋白水解的稳定性。通过将源自十八烷二酸（C18）或二十烷二酸（C20）的白蛋白结合侧链连接到位置 B29 的赖氨酸上，可获得超长的药代动力学特征。对于获得超长 PK 曲线，胰岛素受体亲和力的显著降低也很关键。在狗中的口服生物利用度表明，基于 C18 的类似物优于基于 C20 的类似物。这些研究导致了两种临床候选物 OI338 和 OI320（和，分别）的鉴定。
