ISIS-CRP RX: PHARMACOKINETICS, PHARMACODYNAMICS, SAFETY AND TOLERABILITY OF AN ANTISENSE OLIGONUCLEOTIDE SPECIFIC FOR INHIBITION OF CRP IN INFLAMMATION

Background CRP is elevated in many diseases with inflammatory components such as rheumatoid arthritis, acute coronary syndrome and atrial fibrillation. Elevated CRP levels are associated with increased disease burden and are potentially involved in the propagation of the inflammatory response. Lowering CRP levels could improve disease outcome. ISIS-CRP Rx , an antisense oligonucleotide (ASO) that selectively reduces CRP, distributes rapidly from plasma to tissue, especially liver, has predictable plasma and tissue exposure, half-life of 2-3 weeks, and high tissue bioavailability by s.c. or i.v. administration (Jones, 2012; Yu, 2012). Objectives Characterize PK, PD, safety and tolerability of ISIS-CRP Rx in healthy volunteers; assess effect of ISIS-CRP Rx on the acute phase response following an immune stimulus (endotoxin challenge in healthy volunteers); and evaluate the ability of ISIS-CRP Rx to modulate a chronic inflammatory condition (rheumatoid arthritis) in 3 randomized, double-blind, placebo-controlled trials. Methods 80 healthy volunteers in a Phase 1 clinical study (s.c. and i.v., placebo or up to 600 mg per dose), 35 healthy volunteers in an endotoxin challenge study (placebo, 400 mg and 600 mg i.v. per dose) and 51 RA patients in a 12-week Phase 2, parallel group, multicenter study (placebo, 100 mg, 200 mg and 400 mg s.c. per dose). Results In the Phase 1 study ISIS-CRP Rx produced statistically significant reductions in non-stimulated CRP levels by a median of 76% compared to baseline at the 600 mg dose and was well tolerated at all doses. In the endotoxin challenge study, pretreatment with ISIS-CRP Rx selectively and significantly inhibited the CRP response in a dose-dependent manner, without altering other inflammatory plasma biomarkers or the physiological response to endotoxin. In the Phase 2 RA study there were dose-dependent reductions in CRP (>70% at the 400mg dose) with no serious infections, and no elevations in LFTs, lipids, creatinine or other lab abnormalities related to ISIS-CRP Rx . ACR20 was 20.0% for placebo and 36.4% for ISIS-CRP Rx 400mg at Day 36 while at Day 92 ACR20 was 54.5% in placebo and 36.4% in the 400 mg group. The DAS28 change from baseline at Day 92 was -1.32 for placebo and -1.13 at 400 mg. There was no statistically significant difference versus placebo for these parameters. Conclusions In these studies ISIS-CRP Rx selectively reduced CRP in a rapid manner, and was well tolerated in healthy volunteers and in RA patients. Use of ISIS-CRP Rx in other inflammatory conditions may warrant further exploration. References Jones NR, Pegues MA, McCrory MA, Singleton W, Bethune C, Baker BF, Norris DA, Crooke RM, Graham MJ, Szalai AJ. A selective inhibitor of human C-reactive protein translation is efficacious in vitro and in C-reactive protein transgenic mice and humans. Mol Ther Nucleic Acids. 2012;1:e52. doi: 10.1038/mtna.2012.44. Yu RZ, Grundy JS, Geary. Clinical pharmacokinetics of second generation antisense oligonucleotides. Expert Opin Drug Metab Toxicol. 2013; 9: 169-182. Disclosure of Interest : None declared DOI 10.1136/annrheumdis-2014-eular.2538