Discussion
This study summarizes the phase 2 experience of six GalNAcThe improved safety margin observed is driven by increased potency, which allows lower doses to achieve full activity and less frequent administration. When comparing monthly dosing to more frequent administration, the safety profile is further improved. Monthly dosing showed no effect on mean values over time in ALT levels, serum creatinine levels, or platelet counts across all dose levels tested over a 6- to 12-month treatment period when compared with placebo administration.The most remarkable improvement in less frequent dosing (monthly) was demonstrated by the tolerability profile and near-complete reduction of discontinuations due to AEs. The incidence of discontinuing dosing due to an AE was similar between the total ASO (3.6%) and placebo (4.6%) groups of subjects treated under the monthly dose regimen, with <1% of discontinuations attributed to a local AE at the injection site in ASO-treated subjects. The incidence of LCRIS and related dose discontinuations are reduced in comparison to the unconjugated form of the 2′MOE-modified ASOs [The expansion of safety and tolerability beyond Phase 1 experience in healthy volunteers provides strength to the current body of evidence. Further strength is provided by the inclusion of controlled data from placebo administration in subjects, the number of drugs in this chemical class (of differing sequences, but similar chemistry), and substantial increase in the duration of exposure up to 1 year. In addition to similar chemistry, the GalNAcThe six GalNAc