An oral antisense oligonucleotide for PCSK9 inhibition

Authors: Peter Gennemark, Katrin Walter, Niclas Clemmensen, Dinko Rekić, Catarina Nilsson, Jane Knöchel, Mikko Hölttä, Linda Wernevik, Birgitta Rosengren, Dorota Kakol‐Palm, Yanfeng Wang, Rosie Z. Yu, Richard S. Geary, Stan Riney, Brett P. Monia, Rikard Isaksson, Rasmus Jansson‐Löfmark, Cristina S. J. Rocha, Daniel Lindén, Eva Hurt‐Camejo, Rosanne M. Crooke, Lloyd Tillman, Tina Rydén‐Bergsten, Björn Carlsson, Ulf Andersson, Marie Elebring, Anna Tivesten, Nigel Davies - Science Translational Medicine 2021 cited by 121

-acetylgalactosamine conjugation make this ASO highly potent. A single subcutaneous dose of 90 mg reduced PCSK9 by >90% in humans with elevated LDL cholesterol and a monthly subcutaneous dose of around 25 mg is predicted to reduce PCSK9 by 80% at steady state. To investigate the feasibility of oral administration, the ASO was coformulated in a tablet with sodium caprate as permeation enhancer. Repeated oral daily dosing in dogs resulted in a bioavailability of 7% in the liver (target organ), about fivefold greater than the plasma bioavailability. Target engagement after oral administration was confirmed by intrajejunal administration of a rat-specific surrogate ASO in solution with the enhancer to rats and by plasma PCSK9 and LDL cholesterol lowering in cynomolgus monkey after tablet administration. On the basis of an assumption of 5% liver bioavailability after oral administration in humans, a daily dose of 15 mg is predicted to reduce circulating PCSK9 by 80% at steady state, supporting the development of the compound for oral administration to treat dyslipidemia.