Year-end Sale % OFF 
Abstract
Acid sphingomyelinase deficiency (ASMD; Niemann-Pick disease type A and B) is a lysosomal storage disorder characterized by abnormal intracellular sphingomyelin (SM) accumulation. Prominent liver involvement results in hepatomegaly, fibrosis/cirrhosis, abnormal liver chemistries, and a proatherogenic lipid profile. Olipudase alfa (recombinant human ASM) is in clinical development as an investigational enzyme replacement therapy for the non-neurological manifestations of ASMD. In a phase 1b study conducted to evaluate the safety and tolerability of within-patient dose escalation with olipudase alfa, measurement of SM levels in liver biopsies was used as a pharmacodynamic biomarker of substrate burden. Five adult patients with non neuronopathic ASMD received escalating doses of olipudase alfa every 2 weeks for 26 weeks. Liver biopsies obtained at baseline and 26 weeks after treatment were evaluated for SM storage by histomorphometric analysis, biochemistry, and electron microscopy. Biopsies were also assessed for inflammation and fibrosis, and for the association of SM levels with liver volume, liver function tests, and lipid profiles. At baseline, SM storage present in Kupffer cells and hepatocytes ranged from 9.8% to 53.8% of the microscopic field. After 26 weeks of treatment, statistically significant reductions in SM (P<0.0001) measured by morphometry were seen in 4 patients with evaluable liver biopsies. The 26-week biopsy of the fifth patient was insufficient for morphometric quantitation. Posttreatment SM levels ranged from 1.2% to 9.5% of the microscopic field, corresponding to an 84% to 92% relative reduction from baseline. Improvements in liver volume, liver function tests, and lipid profiles were also observed. This study illustrates the utility of SM assessment by liver biopsy as a pharmacodynamic biomarker of disease burden in these patients.
Highlights
Acid sphingomyelinase deficiency (ASMD; NiemannPick disease type A and B) is a lysosomal storage disorder characterized by abnormal intracellular sphingomyelin (SM) accumulation
The hepatomegaly that develops as a result of longstanding ASMD is a significant cause of morbidity and mortality leading to cirrhosis, liver failure, and death.[2,3]
We previously reported detailed liver pathology on 17 ASMD patients enrolled in a phase 1 single ascending dose trial of olipudase alfa.[25,26]
Summary
Acid sphingomyelinase deficiency (ASMD; NiemannPick disease type A and B) is a lysosomal storage disorder characterized by abnormal intracellular sphingomyelin (SM) accumulation. In a phase 1b study conducted to evaluate the safety and tolerability of within-patient dose escalation with olipudase alfa, measurement of SM levels in liver biopsies was used as a pharmacodynamic biomarker of substrate burden. Acid sphingomyelinase deficiency (ASMD) is a rare lysosomal storage disorder characterized by the pathologic accumulation of sphingomyelin (SM) in cells throughout the body, primarily within the liver, spleen, lungs, and bone marrow, leading to significant clinical disease. The hepatomegaly that develops as a result of longstanding ASMD is a significant cause of morbidity and mortality leading to cirrhosis, liver failure, and death.[2,3] SM accumulation occurs within the lysosomes of both macrophage-derived Kupffer cells (foam cells) and in hepatocytes where it cocrystalizes in lamellar structures with cholesterol.[3] The liver is a major organ involved in lipoprotein biogenesis, metabolism, and lipid homeostasis.[4,5] massive hepatocellular accumulation of SM6 is likely to perturb normal cell function and lead to derangements in lipid homeostasis. Natural history studies of patients with ASMD have shown that the
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
