Molecular engineering of safe and efficacious oral basal insulin

Frantisek Hubálek, Hanne H. F. Refsgaard, Sanne Gram-Nielsen, Peter Madsen, Erica Nishimura, Martin Münzel, Christian Lehn Brand, Carsten Enggaard Stidsen, Christian Hove Claussen, Erik Max Wulff, Lone Pridal, Ulla Ribel, Jonas Kildegaard, Trine Porsgaard, Eva Johansson, Dorte Bjerre Steensgaard, Lars Hovgaard, Tine Glendorf, Bo Falck Hansen, Maja Kirkegaard Jensen, Peter Kresten Nielsen, Svend Ludvigsen, Susanne Rugh, Patrick W. Garibay, Mary Courtney Moore, Alan D. Cherrington and Thomas Kjeldsen ()
Additional contact information
Frantisek Hubálek: Novo Nordisk A/S, Novo Nordisk Park 1
Hanne H. F. Refsgaard: Novo Nordisk A/S, Novo Nordisk Park 1
Sanne Gram-Nielsen: Novo Nordisk A/S, Novo Nordisk Park 1
Peter Madsen: Novo Nordisk A/S, Novo Nordisk Park 1
Erica Nishimura: Novo Nordisk A/S, Novo Nordisk Park 1
Martin Münzel: Novo Nordisk A/S, Novo Nordisk Park 1
Christian Lehn Brand: Novo Nordisk A/S, Novo Nordisk Park 1
Carsten Enggaard Stidsen: Novo Nordisk A/S, Novo Nordisk Park 1
Christian Hove Claussen: Novo Nordisk A/S, Novo Nordisk Park 1
Erik Max Wulff: Novo Nordisk A/S, Novo Nordisk Park 1
Lone Pridal: Novo Nordisk A/S, Novo Nordisk Park 1
Ulla Ribel: Novo Nordisk A/S, Novo Nordisk Park 1
Jonas Kildegaard: Novo Nordisk A/S, Novo Nordisk Park 1
Trine Porsgaard: Novo Nordisk A/S, Novo Nordisk Park 1
Eva Johansson: Novo Nordisk A/S, Novo Nordisk Park 1
Dorte Bjerre Steensgaard: Novo Nordisk A/S, Novo Nordisk Park 1
Lars Hovgaard: Novo Nordisk A/S, Novo Nordisk Park 1
Tine Glendorf: Novo Nordisk A/S, Novo Nordisk Park 1
Bo Falck Hansen: Novo Nordisk A/S, Novo Nordisk Park 1
Maja Kirkegaard Jensen: Novo Nordisk A/S, Novo Nordisk Park 1
Peter Kresten Nielsen: Novo Nordisk A/S, Novo Nordisk Park 1
Svend Ludvigsen: Novo Nordisk A/S, Novo Nordisk Park 1
Susanne Rugh: Novo Nordisk A/S, Novo Nordisk Park 1
Patrick W. Garibay: Novo Nordisk A/S, Novo Nordisk Park 1
Mary Courtney Moore: Vanderbilt University
Alan D. Cherrington: Vanderbilt University
Thomas Kjeldsen: Novo Nordisk A/S, Novo Nordisk Park 1

Nature Communications, 2020, vol. 11, issue 1, 1-9

Abstract: 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.

Date: 2020
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-17487-9

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DOI: 10.1038/s41467-020-17487-9

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