Acid sphingomyelinase deficiency (ASMD; Niemann-Pick Disease type A and B) is characterised by sphingomyelin accumulation resulting in a range of systemic manifestations including pro-atherogenic lipid profile. Olipudase alfa is an enzyme replacement therapy (ERT) in clinical development for treatment of systemic manifestations of ASMD. The aim of this study was to assess the impact of olipudase alfa on PCSK9 concentration, lipoproteins and markers on inflammation. 
Escalating doses of olipudase alfa was administered 2-weekly for 26weeks in 5 adults with ASMD as part of a phase 1b clinical trial. Lipid profile and inflammatory markers were measured and compared to 15 healthy control participants.
Patients with ASMD had higher triglyceride [median(interquartile range, IQR); 1.6(1.2–3.6) vs 0.9(0.7–1.1)mmol/l; P=0.004], apoB-100 [0.87(0.77–1.16) vs 0.66(0.59–0.78); P=0.019], apoB-48 [88.3(79.9–100.5) vs 60.6(51.0–71.7; P=0.001] and lower HDL-C [0.64(0.62 – 1.04) vs 1.27(1.06 – 1.41)mmol/l; P=0.005] and lower apoAI [0.72(0.65–1.08) vs 1.27(1.06–1.41); P=0.001) compared to controls. Total cholesterol (meanstandard deviation, SD; 18.320.4%), triglyceride (46.917.3), LDL-C (16.222.1%), apoB-100 (-18.420.4%) and PCSK9 (10.029.1) decreased following ERT. The percentage change (%) in apoB-100 correlated with %PCSK9 (=0.900, P=0.037). TNF- was higher in ASMD at baseline compared to controls [78.7(65.2–85.5) vs 28.4(20.7–36.3); P<0.001] and this improved significantly following ERT [54.2(20.8–60.3) at 26 weeks; P=0.043].
ERT in ASMD results in improvements in lipid profile and reduction in systemic inflammation. ApoB-100 decreased in association with PCSK9, suggesting increased clearance of apoB-containing lipoproteins by LDL receptors as a result of reduction in PCSK9.

06 - APOLIPOPROTEIN B-100 DECREASES IN ASSOCIATION WITH REDUCTION IN PCSK9 CONCENTRATION IN ACID SPHINGOMYELINASE DEFICIENCY FOLLOWING ENZYME REPLACEMENT THERAPY