Safety assessment of drug impurities is a routine part of the drug development process. For oligonucleotide-based drugs, impurities can arise from impurities in starting materials, as by-products of the manufacturing process or from degradation, and are generally structurally similar to the parent oligonucleotide. To study the potential impact of impurities, a representative batch of a 2'-O-methoxyethyl (MOE) antisense oligonucleotide (ASO) was compared to batches of drug that were enriched with nine of the common impurities encountered with the chemical class. Mice were treated for 3 months with weekly subcutaneous injection of 10 or 30 mg/kg. The impurity content of the parent batch was 0.25%-2.5% of total drug substance. The enriched impurity mixtures contained from 3% to 10% of the various impurities. The expected common class effects were observed at the 30 mg/kg/week dose level in hematology, serum chemistry, and histopathology. However, there were no differences between the representative batch of material and those enriched with impurities. Based on these data, common oligonucleotide impurity studies do not appear to contribute to the overall toxicology profile.
Keywords: impurity; modified antisense inhibitor; mouse; qualification; toxicology.