Long-term efficacy of olipudase alfa in adults with acid sphingomyelinase deficiency (ASMD): Further clearance of hepatic sphingomyelin is associated with additional improvements in pro- and anti-atherogenic lipid profiles after 42 months of treatment

Mol Genet Metab. Sep-Oct 2020;131(1-2):245-252. doi: 10.1016/j.ymgme.2020.06.010. Epub 2020 Jun 24.

PMID: 32620536

Beth L Thurberg, George A Diaz, Robin H Lachmann, Thomas Schiano, Melissa P Wasserstein, Allena J Ji, Atef Zaher, M Judith Peterschmitt

Summary: This is a 26-week phase 1b trial of enzyme replacement therapy (ERT) with olipudase alfa, which was followed by a long-term extension study. 5 adult patients with chronic visceral ASMD were enrolled in this trial. The findings show that hepatic clearance of sphingomyelin during olipudase alfa treatment for 42 months is associated with overall lipid profile improvements in ASMD patients.

Abstract

Background: Lipoprotein synthesis and metabolism take place primarily in the liver. Hepatomegaly, fibrosis, elevated liver enzymes, and a pro-atherogenic lipid profile are all symptoms of chronic visceral ASMD. Pharmacodynamic biomarkers included sphingomyelin (SM) levels in liver biopsies and lyso-SM levels in plasma.

Methods: Five adult patients with chronic visceral ASMD were enrolled in a 26-week phase 1b trial of enzyme replacement therapy (ERT) with olipudase alfa (NCT01722526), which was followed by a long-term extension study (NCT02004704). After 42 months of treatment period, the changes are compared in hepatic SM levels, plasma lyso-SM, and lipoprotein profiles.

Results: Throughout the trial, progressive clearance of histologic SM storage was observed, as well as similar reductions in plasma lyso-SM. Improvements in liver enzymes were observed at 6 months and remained stable at 42 months. At months 6 and 42, pro-atherogenic lipid profiles (total cholesterol, LDL-C, VLDL-C, triglycerides) showed progressive reductions from baseline. Conversely, anti-atherogenic markers, HDL-C and apolipoprotein A-I, increased over time, with HDL-C increasing by up to 200% over baseline levels after 42 months of treatment.

Conclusion: These findings show that hepatic clearance of SM during olipudase alfa treatment for 42 months is associated with overall lipid profile improvements in ASMD patients. The clinical significance of these results will have to be determined in the future, but it is speculated that these improvements may lower the risk of liver cirrhosis and cardiovascular disease.