Molecular Engineering of Insulin Icodec, the First Acylated Insulin Analog for Once-Weekly Administration in Humans
Thomas Kjeldsen, František Hubálek, Claudia U. Hjørringgaard, Tina M. Tagmose, Erica Nishimura, Carsten E. Stidsen, Trine Porsgaard, Christian Fledelius, Hanne H. F. Refsgaard, Sanne Gram-Nielsen, Helle Naver, Lone Pridal, Thomas Høeg-Jensen, Claus Jeppesen, Valentina Manfé, Svend Ludvigsen, Inger Lautrup-Larsen, Peter Madsen
Abstract
Here, we describe the molecular engineering of insulin icodec to achieve a plasma half-life of 196 h in humans, suitable for once-weekly subcutaneously administration. Insulin icodec is based on re-engineering of the ultra-long oral basal insulin OI338 with a plasma half-life of 70 h in humans. This systematic re-engineering was accomplished by (1) further increasing the albumin binding by changing the fatty diacid from a 1,18-octadecanedioic acid (C18) to a 1,20-icosanedioic acid (C20) and (2) further reducing the insulin receptor affinity by the B16Tyr → His substitution. Insulin icodec was selected by screening for long intravenous plasma half-life in dogs while ensuring glucose-lowering potency following subcutaneous administration in rats. The ensuing structure-activity relationship resulted in insulin icodec. In phase-2 clinical trial, once-weekly insulin icodec provided safe and efficacious glycemic control comparable to once-daily insulin glargine in type 2 diabetes patients. The structure-activity relationship study leading to insulin icodec is presented here.