Engineering of Orally Available, Ultralong-Acting Insulin Analogues: Discovery of OI338 and OI320

• Published in: Journal of medicinal chemistry Vol. 64; no. 1; pp. 616 - 628
• Main Authors: Kjeldsen, Thomas B, Hubálek, František, Tagmose, Tina M, Pridal, Lone, Refsgaard, Hanne H F, Porsgaard, Trine, Gram-Nielsen, Sanne, Hovgaard, Lars, Valore, Henrik, Münzel, Martin, Hjørringgaard, Claudia U, Jeppesen, Claus Bekker, Manfè, Valentina, Hoeg-Jensen, Thomas, Ludvigsen, Svend, Nielsen, Peter Kresten, Lautrup-Larsen, Inger, Stidsen, Carsten E, Wulff, Erik M, Garibay, Patrick W, Kodra, János T, Nishimura, Erica, Madsen, Peter
• Format: Journal Article
• Language: English
• Published: United States 14-01-2021
• Subjects: Acylation; Administration, Oral; Amino Acid Sequence; Animals; Biological Availability; Delayed-Action Preparations; Dogs; Half-Life; Humans; Hypoglycemic Agents - administration & dosage; Hypoglycemic Agents - pharmacokinetics; Insulin - administration & dosage; Insulin - chemistry; Insulin - pharmacokinetics; Rats
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.0c01576

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).