The Effects of 2-O-Methoxyethyl Oligonucleotides on Renal Function in Humans

Systemically administered 2-O-methoxyethyl (2MOE) antisense oligonucleotides (ASOs) accumulate in the kidney and metabolites are cleared in urine. The effects of eleven 2MOE ASOs on renal function were assessed in 2,435 patients from 32 phase 2 and phase 3 trials. The principle analysis was on data from 28 randomized placebo-controlled trials. Mean levels of renal parameters remained within normal ranges over time across dose groups. Patient-level meta-analyses demonstrated a significant difference between placebo-treated and 2MOE ASO-treated patients at doses >175mg/week in the percentage and absolute change from baseline for serum creatinine and estimated glomerular filtration rate. However, these changes were not clinically significant or progressive. No dose-related effects were observed in the incidence of abnormal renal test results in the total population of patients, or subpopulation of diabetic patients or patients with renal dysfunction at baseline. The incidence of acute kidney injury [serum creatinine 0.3mg/dL (26.5M) increases from baseline or 1.5xbaseline] in 2MOE ASO-treated patients (2.4%) was not statistically different from placebo (1.7%, P=0.411). In conclusion, in this database, encompassing 32 clinical trials and 11 different 2MOE ASOs, we found no evidence of clinically significant renal dysfunction up to 52 weeks of randomized-controlled treatment.