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.

Autor: Thurberg BL; Department of Pathology, Sanofi Genzyme, Cambridge, MA, United States of America. Electronic address: Beth.Thurberg@sanofi.com., Diaz GA; Genetics and Genomics Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America., Lachmann RH; National Hospital for Neurology and Neurosurgery, London, UK., Schiano T; Genetics and Genomics Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America., Wasserstein MP; Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, NY, United States of America., Ji AJ; Biomarkers and Clinical Bioanalysis, Sanofi Genzyme, Framingham, MA, United States of America., Zaher A; Clinical Development, Sanofi Genzyme, Cambridge, MA, United States of America., Peterschmitt MJ; Clinical Development, Sanofi Genzyme, Cambridge, MA, United States of America.
Jazyk: angličtina
Zdroj: Molecular genetics and metabolism [Mol Genet Metab] 2020 Sep - Oct; Vol. 131 (1-2), pp. 245-252. Date of Electronic Publication: 2020 Jun 24.
DOI: 10.1016/j.ymgme.2020.06.010
Abstrakt: The liver is a major site of lipoprotein synthesis and metabolism. Liver manifestations of chronic visceral ASMD include hepatomegaly, fibrosis, elevated liver enzymes and a pro-atherogenic lipid profile. Measurements of sphingomyelin (SM) levels in liver biopsies and lyso-SM in plasma were used as pharmacodynamic biomarkers. 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) followed by an ongoing long-term extension study (NCT02004704). We compare the changes in hepatic SM levels, plasma lyso-SM, and lipoprotein profiles after 42 months of treatment. Progressive clearance of histologic SM storage was observed throughout the trial, along with similar reductions in plasma lyso-SM. Improvements in liver enzymes were observed at 6 months and remained stable at 42 months. Progressive reductions from baseline in pro-atherogenic lipid profiles (total cholesterol, LDL-C, VLDL-C, triglycerides) were observed at month 6 and 42. Conversely, there were progressive increases in anti-atherogenic markers, HDL-C and apolipoprotein A-I, with HDL-C increases up to 200% over baseline levels after 42 months of treatment. These data demonstrate that hepatic clearance of SM during olipudase alfa treatment over 42 months is associated with overall improvements in the lipid profiles of ASMD patients. The clinical relevance of these findings needs to be determined in the future, but we speculate that these improvements may reduce the risk for liver cirrhosis and cardiovascular disease. Trial registration: Clintrials.gov trial registration # NCT01722526.
(Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: