Fig. 4.

Preclinical and clinical performance of siRNAs with comprehensive modification chemistries. a Sense and antisense strand optimization by using transthyretin (Ttr)-targeting siRNAs and the combinatorial designs explored across 10 siRNAs. The effect relative to the parent is described as the model-adjusted mean difference in the activity of the design variant (DV) compared to the parent. b–d The liver exposure, RISC loading, and silencing activities of the parent, DV18, and fully 2′-OMe conjugates. Data are shown as the mean ± SD. e Gene-silencing duration of antithrombin-targeted siRNAs modified with the designs of patent and DV22 evaluated in Cynomolgus monkeys (n = 3 per group). Asterisks indicate that a significant difference was observed between the parent and DV22. Error is shown as the SD. f C5 knockdown profile after applying a single dose of Cemdisiran that employs ESC modification in a phase 1/2 clinical study. Error is represented as the SEM. a–e Copyright of Elsevier Inc., 2018. f Copyright of Alnylam Pharmaceuticals, 2016