Assessment of the Effects of 2′-Methoxyethyl Antisense Oligonucleotides on Platelet Count in Cynomolgus Nonhuman Primates

Decreases in platelet (PLT) counts observed in nonhuman primates (NHPs) given 2′-O-methoxyethyl modified antisense inhibitors (2′-MOE ASOs) have been reported, but the incidence and severity of the change vary considerably between sequences, studies, and animals. This article will broadly illustrate the spectrum of effects on PLT count in NHPs. From queries of an NHP safety database representing over 102 independent 2′-MOE ASOs, from 61 studies and >2200 NHPs, two patterns of PLT changes emerged. The first is a consistent and reproducible decrease in group mean values, observed with about 30% of the compounds, in which PLT count typically remains ≥150K cells/μL. The second is a sporadic decrease in PLTs to 5 mg/kg) that is often not reproducible. In both cases, the reduction in PLT count is dose dependent and reversible. The human relevance of PLT change observed in NHPs was investigated using ISIS 404173. In a chronic NHP study (20 mg/kg/wk for 26 weeks), a gradual decrease in group mean PLT count was observed at ≥10 mg/kg/wk, which plateaued by 13 weeks generally within the normal range and was maintained through 26 weeks of treatment. However, PLT counts 30% decreased compared to baseline but no incidence of PLT