Toxicological and Pharmacokinetic Properties of QPI-1007, a Chemically Modified Synthetic siRNA Targeting Caspase 2 mRNA, Following Intravitreal Injection

• Published in: Nucleic acid therapeutics Vol. 24; no. 4; pp. 258 - 266
• Main Authors: Solano, Elisabeth C.R., Kornbrust, Douglas J., Beaudry, Amber, Foy, Jeffrey W.-D., Schneider, David J., Thompson, James D.
• Format: Journal Article
• Language: English
• Published: United States Mary Ann Liebert, Inc 01.08.2014
• Subjects: Animals; Brain Waves - physiology; Caspase 2 - genetics; Caspase 2 - metabolism; Clinical trials; Drug Administration Schedule; Female; Injection; Injections; Injections, Intravenous; Intravitreal Injections; Kinetics; Lethal Dose 50; Male; Molecular Targeted Therapy; Original Articles; Pharmacokinetics; Pharmacology; Rabbits; Rats; Rats, Sprague-Dawley; Retina - metabolism; Ribonucleic acid; RNA; RNA, Messenger - antagonists & inhibitors; RNA, Messenger - genetics; RNA, Messenger - metabolism; RNA, Small Interfering - chemical synthesis; RNA, Small Interfering - genetics; RNA, Small Interfering - metabolism; RNA, Small Interfering - pharmacokinetics; Toxicology
• ISSN: 2159-3337; 2159-3345
• DOI: 10.1089/nat.2014.0489

We report the toxicological and pharmacokinetic properties of the synthetic, small interfering RNA (siRNA), QPI-1007, following intravitreal administration. QPI-1007 is a chemically modified siRNA designed to act via the RNA interference (RNAi) pathway to temporarily inhibit expression of the caspase 2 protein and is being developed as a neuroprotectant for the treatment of nonarteritic anterior ischemic optic neuropathy and other optic neuropathies such as glaucoma that result in the death of retinal ganglion cells. The half-life of QPI-1007 in the vitreous and retina/choroid in the Dutch Belted rabbit was about 2 days, and there was no sign of accumulation after repeated administrations at either 2- or 4-week dosing intervals in the rabbit. QPI-1007 was well tolerated in Dutch Belted rabbits following single or repeated intravitreal administrations of up to 11 doses over 9 months. Test-article–related effects were limited to the eyes, with minimal to mild vitreal cellular infiltration being the major finding, which was reversible. In repeated-dose studies, a modest reduction in B-wave amplitude obtained by electroretinography was observed in animals treated with the highest dose level tested (3 mg, which is equivalent to a 12 mg/eye human dose) that was not considered to be clinically meaningful. Administration in the rat of either a single bolus intravenous (i.v.) injection of 100 mg/kg or daily bolus i.v. injections of 75 mg/kg/day for 28 days failed to elicit any macroscopic or microscopic changes, suggesting a low risk for systemic toxicity. QPI-1007 was negative in three genetic toxicity studies. Overall, the nonclinical studies support the further development of QPI-1007.