Abstract 10469: Time Averaged Lipoprotein(a) Reduction With Sln360, a Novel Sirna Targeting Lp(a,) in Healthy Adults With Elevated Lp(a)

Introduction: Lipoprotein(a) [Lp(a)] is an important risk factor for atherothrombotic cardiovascular disease for which there are no approved drugs. SLN360 is a short interfering RNA (siRNA) designed to reduce hepatic production of apolipoprotein(a). Primary safety, tolerability and Lp(a) lowering effects have previously been reported in a phase 1 single ascending dose study. Methods: Adults with Lp(a) plasma concentrations ≥ 150 nmol/L at entry and no clinically overt cardiovascular disease were randomized to receive a subcutaneous dose of SLN360 or placebo. The primary efficacy evaluation was percent reduction in Lp(a). Time-averaged reductions were determined to further inform dosing frequency and better evaluate potential clinical benefits. Results: Thirty-two adults received study drug in 4 cohorts. Large, dose-dependent reductions in Lp(a) were observed. For the top 2 doses (300 mg and 600 mg), median (IQR) maximal reductions of 96% (89%, 98%) and 98% (97%, 98%), with reductions of 71% and 81% persisting to day 150, respectively. The time-averaged effect from administration to 150 days, including the time to reach the Lp(a) nadir, was 82% and 87% for the 300 mg and 600 mg groups, respectively. To reflect the anticipated effects of repeat dosing, additional analyses excluded the time to achieve Lp(a) nadir (the first 30 days). This analysis showed 85% and 92% time-averaged median reductions in the 300 mg and 600 mg doses, respectively. Conclusions: In adults with elevated Lp(a), single doses of SLN360 substantially reduced Lp(a) with observed median maximal percent lowering of >95% for doses of 300mg and above, with effects persisting for 150 days. Median time-averaged reductions during 150 days of follow up exceeded 80% in 300 mg and 600 mg treatment groups. Infrequent SLN360 dosing has the potential to substantially reduce Lp(a) to clinically meaningful levels.