title: From the Cover: The Minipig is a Suitable Non-Rodent Model in the Safety Assessment of Single Stranded Oligonucleotides.
abstract: Non-human primates (NHPs) are currently considered to be the non-rodent species of choice for the preclinical safety assessment of single-stranded oligonucleotide (SSO) drugs. We evaluated minipigs as a potential alternative to NHPs to test the safety of this class of compounds. Four different phosphorothioated locked nucleic acid-based SSOs (3 antisense and 1 anti-miR), all with known safety profiles, were administered to minipigs using similar study designs and read-outs as in earlier NHP studies with the same compounds. The studies included toxicokinetic investigations, in-life monitoring, clinical and anatomic pathology. In the minipig, we demonstrated target engagement by the SSOs where relevant, and a similar toxicokinetic behavior in plasma, kidney, and liver when compared with NHPs. Clinical tolerability was similar between minipig and NHPs. For the first time, we showed similar and dose-dependent effects on the coagulation and complement cascade after intravenous dosing similar to those observed in NHPs. Similar to NHPs, morphological changes were seen in proximal tubular epithelial cells of the kidney, Kupffer cells, hepatocytes, and lymph nodes. Minipigs appeared more sensitive to the high-dose kidney toxicity of most of the selected SSOs than NHPs. No new target organ or off-target toxicities were identified in the minipig. The minipig did not predict the clinical features of human injection site reactions better than the NHPs, but histopathological similarities were observed between minipigs and NHPs. We conclude that there is no impediment, as default, to the use of minipigs as the non-rodent species in SSO candidate non-clinical safety packages.
authors.affiliation: Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Braendli-Baiocco
authors.affiliation: Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
authors.forename: Matthias
authors.initials: M
authors.lastname: Festag
authors.affiliation: Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Copenhagen, Hørsholm, Denmark.
authors.forename: Kamille
authors.initials: K
authors.lastname: Dumong Erichsen
authors.affiliation: Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Copenhagen, Hørsholm, Denmark.
authors.forename: Robert
authors.initials: R
authors.lastname: Persson
authors.affiliation: University Hospital Basel, Institute for Pathology, Basel, Switzerland.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Mihatsch
authors.affiliation: Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Copenhagen, Hørsholm, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Fisker
authors.affiliation: Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
authors.forename: Juergen
authors.initials: J
authors.lastname: Funk
authors.affiliation: Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
authors.forename: Susanne
authors.initials: S
authors.lastname: Mohr
authors.affiliation: Roche Pharmaceutical Research and Early Development, Bioanalytical Research and Development, Roche Innovation Center Munich, Roche Diagnostics GmbH, Penzberg, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Constien
authors.affiliation: Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
authors.forename: Corinne
authors.initials: C
authors.lastname: Ploix
authors.affiliation: Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
authors.forename: Kevin
authors.initials: K
authors.lastname: Brady
authors.affiliation: Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
authors.forename: Marco
authors.initials: M
authors.lastname: Berrera
authors.affiliation: Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
authors.forename: Bernd
authors.initials: B
authors.lastname: Altmann
authors.affiliation: Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Lenz
authors.affiliation: Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center New York, F. Hoffmann-La Roche Ltd, New York, NY, USA.
authors.forename: Mudher
authors.initials: M
authors.lastname: Albassam
authors.affiliation: Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
authors.forename: Georg
authors.initials: G
authors.lastname: Schmitt
authors.affiliation: Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Weiser
authors.affiliation: Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
authors.forename: Franz
authors.initials: F
authors.lastname: Schuler
authors.affiliation: Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Singer
authors.affiliation: Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Copenhagen, Hørsholm, Denmark.
authors.forename: Yann
authors.initials: Y
authors.lastname: Tessier
mesh_terms: D000818:Animals; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D005260:Female; D023421:Models, Animal; D009841:Oligonucleotides / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D013552:Swine; D013556:Swine, Miniature; D014018:Tissue Distribution; D066007:Toxicokinetics
chemical_list: D009841:Oligonucleotides
keywords: locked nucleic acid; minipig; non-human primate; single-stranded oligonucleotide; safety assessment