Preclinical and Clinical Development of Long-acting Amylin Agonists
Thomas Kruse
Senior Principal Scientist, Novo Nordisk
Amylin is a 37 amino acid long peptide produced in pancreatic beta-cells and co-secreted with insulin. Human amylin has high propensity for fibrillation and is involved in amyloid formation in islets as part of the pathology of T2 diabetes. Pramlintide, a short-acting amylin analogue, has been on the market since 2005 and has demonstrated efficacy on glucose control and body weight in combination with insulin but require injection three times a day.
Amylin binds to and activate the calcitonin receptor, eventually in complex with RAMP1-3 (AmyR1-3). Analogues of calcitonin are therefore an alternative starting point for development of amylin agonists.
This talk focus on the ongoing efforts at Novo Nordisk to further develop the pharmacological utility of amylin agonists using lipidation as a tool to prolong the duration of action. The initial effort highlights the SAR of:
A) Unselective, amylin-based agonists leading to cagrilintide (AM833) as a clinical candidate.
B) AmyR selective, amylin-based agonists (NN1213)
C) Unselective, calcitonin-based agonists (NN1558) with focus on co-formulation at neutral pH.
The SAR and challenges that relate to chemical and physical stability of formulations of amylin analogues are discussed along with highlights from the clinical development of cagrilintide.
Thomas Kruse received a PhD in chemistry/biology in 1992 from Odense University, working on electroactive molecular sensors with Professor Jan Becher and Professor Michael Cava from the University of Alabama. He did postdoctoral work at the University of Durham working with Professor Martin Bryce. Since 1993, he has been employed by Novo Nordisk in Copenhagen, currently as senior principal scientist. Initially, Thomas worked as small-molecule medicinal chemist, and then in 2002 he switched to peptide chemistry where he led the chemistry effort leading to semaglutide. He has since worked with a variety of metabolic peptides including insulin, CCK, glucagon, and amylin, leading to a number of clinical candidates currently in various stages of clinical development.