Molecular engineering of safe and efficacious oral basal insulin

Abstract

Recently, the clinical proof of concept for the first ultra-long oral insulin was reported, showing efficacy and safety similar to subcutaneously administered insulin glargine. Here, we report the molecular engineering as well as biological and pharmacological properties of these insulin analogues. Molecules were designed to have ultra-long pharmacokinetic profile to minimize variability in plasma exposure. Elimination plasma half-life of ~20 h in dogs and ~70 h in man is achieved by a strong albumin binding, and by lowering the insulin receptor affinity 500-fold to slow down receptor mediated clearance. These insulin analogues still stimulate efficient glucose disposal in rats, pigs and dogs during constant intravenous infusion and euglycemic clamp conditions. The albumin binding facilitates initial high plasma exposure with a concomitant delay in distribution to peripheral tissues. This slow appearance in the periphery mediates an early transient hepato-centric insulin action and blunts hypoglycaemia in dogs in response to overdosing.

Commemorating insulin's centennial: engineering insulin pharmacology towards physiology

“…Liver, muscle and adipose tissue Oral insulin 338 (OI338) has been formulated in a tablet with the absorption enhancer sodium caprate (Figure 2D) [55]. In contrast to currently available basal insulin analogs that are primarily protracted in the s.c. tissue after injection, OI338 is based on protraction in the plasma compartment and the interstitial fluid [55].…”

“…Liver, muscle and adipose tissue Oral insulin 338 (OI338) has been formulated in a tablet with the absorption enhancer sodium caprate (Figure 2D) [55]. In contrast to currently available basal insulin analogs that are primarily protracted in the s.c. tissue after injection, OI338 is based on protraction in the plasma compartment and the interstitial fluid [55]. Molecular engineering of OI338 combined enhanced proteolytic stability, that significantly improves bioavailability, with strong but reversible albumin binding and very low receptor affinity (500-fold reduced vs human insulin), leading to a half-life of~70 h in man [51,55,56].…”

“…In contrast to currently available basal insulin analogs that are primarily protracted in the s.c. tissue after injection, OI338 is based on protraction in the plasma compartment and the interstitial fluid [55]. Molecular engineering of OI338 combined enhanced proteolytic stability, that significantly improves bioavailability, with strong but reversible albumin binding and very low receptor affinity (500-fold reduced vs human insulin), leading to a half-life of~70 h in man [51,55,56]. Specifically, the ultra-long half-life was achieved by slowing receptor-mediated clearance through lowering the IR affinity by replacing two solvent-exposed aromatic amino acids (A14Glu and B25His) and by albumin binding through chemical modification of the ε-amino group of B29Lys with a side chain including a C18 fatty diacid moiety (Figure 2E) [56].…”

“…Specifically, the ultra-long half-life was achieved by slowing receptor-mediated clearance through lowering the IR affinity by replacing two solvent-exposed aromatic amino acids (A14Glu and B25His) and by albumin binding through chemical modification of the ε-amino group of B29Lys with a side chain including a C18 fatty diacid moiety (Figure 2E) [56]. Despite low in vitro potency, OI338 is still a full IR agonist and maintains in vivo efficacy, as demonstrated by whole-body glucose disposal under euglycemic clamp conditions in rats, pigs, and dogs [55]. Rapid absorption and albumin binding contribute to an initial high plasma exposure after oral administration, with a concomitant delay in distribution to peripheral tissues.…”

Review: Glucose-sensitive insulin

“…Chemical changes to insulin have provided analogues with better basal and bolus profiles [ [12] , [13] , [14] ], but they still occasionally result in hypoglycaemia. The latest developments are once-weekly insulin [ 15 ] and attempts at oral basal insulin [ 16 , 17 ], but these projects are striving towards dosing convenience and thus patient compliance more than hypoglycaemia safety. The first reports on glucose-sensitive insulin preparations (GSI) appeared in the 1970s, and they have since been followed by thousands of publications and patent applications.…”