Integrated Safety Assessment of 2′-O-Methoxyethyl Chimeric Antisense Oligonucleotides in NonHuman Primates and Healthy Human Volunteers

Abstract

The common chemical and biological properties of antisense oligonucleotides provide the opportunity to identify and characterize chemical class effects across species. The chemical class that has proven to be the most versatile and best characterized is the 2′-O-methoxyethyl chimeric antisense oligonucleotides. In this report we present an integrated safety assessment of data obtained from controlled dose-ranging studies in nonhuman primates (macaques) and healthy human volunteers for 12 unique 2′-O-methoxyethyl chimeric antisense oligonucleotides. Safety was assessed by the incidence of safety signals in standardized laboratory tests for kidney and liver function, hematology, and complement activation; as well as by the mean test results as a function of dose level over time. At high doses a number of toxicities were observed in nonhuman primates. However, no class safety effects were identified in healthy human volunteers from this integrated data analysis. Effects on complement in nonhuman primates were not observed in humans. Nonhuman primates predicted safe doses in humans, but over predicted risk of complement activation and effects on platelets. Although limited to a single chemical class, comparisons from this analysis are considered valid and accurate based on the carefully controlled setting for the specified study populations and within the total exposures studied.

A Randomized, Double‐Blind, Placebo‐Controlled, First‐Time‐in‐Human Study to Assess the Safety, Tolerability, and Pharmacokinetics of Single and Multiple Ascending Doses of GSK3389404 in Healthy Subjects

“…[21][22][23] An integrated safety assessment of 2 -O-methoxyethyl ASOs across studies of nonhuman primates (NHPs; n = 710) and humans (n = 750) evaluated potential class safety effects. 23 The assessment showed no evidence of drug-associated effects on renal or hepatic function in NHPs or humans. NHPs did show evidence of potential class effects for acute thrombocytopenia and complement activation but are generally considered to be more sensitive to these effects compared with humans.…”

“…PK sampling was also conducted on days 8 and 30 in part 1 and days 8 and 15 in part 2 (predose samples). Following the final study drug administration on day 22 (part 2), serial blood samples were collected predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours postdose (days [22][23][24][25], and on days 29, 36, 50, 71, and 113. Urine samples for assessment of the albumin/creatinine ratio were collected at screening, on day −1, predose, and 24 and 72 hours postdose, and on days 8 and 30 in part 1.…”

Therapeutic Advances for Huntington’s Disease

“…Therefore, the injection of ASOs into the cerebrospinal fluid (CSF) results in ubiquitous delivery of drugs and suppresses the production of mHTT [70] (Table 1). However, ASO delivery has some side effects, like thrombocytopenia which was observed in some human trials of ASOs [113]. ASO can ameliorate transcriptional dysregulation and reduce the level of mHTT and improve behavior in the YAC128, YAC18, and BACHD mouse models of HD [114,115].…”

Safety, tolerability, and pharmacokinetics of radavirsen (AVI‐7100), an antisense oligonucleotide targeting influenza a M1/M2 translation

“…Renal toxicities have been described in the preclinical testing of other antisense oligonucleotides . However, in an integrated safety database across multiple preclinical and clinical studies comprising 710 monkeys and 750 human subjects, there was no evidence of class effect renal toxicities . Furthermore, proteinuria was not reported in other human studies in which a PMO was employed – for example, in exon skipping in Duchenne muscular dystrophy , or with PMOplus® as an antiviral agent in haemorrhagic fever virus infection .…”