Clearance of Hepatic Sphingomyelin by Olipudase Alfa Is Associated With Improvement in Lipid Profiles in Acid Sphingomyelinase Deficiency

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.

The Effects of Liver Transplantation in Children With Niemann‐Pick Disease Type B

“…However, severe complications after HSCT, such as graft‐versus‐host disease and renal tubular dysfunction, are of concern . Meanwhile, enzyme replacement therapy using olipudase alfa for treating adult patients with visceral NPD type B is safe and effective in relieving the clinical presentations . However, its application in pediatric patients is yet to be confirmed.…”

“…(1) Meanwhile, enzyme replacement therapy using olipudase alfa for treating adult patients with visceral NPD type B is safe and effective in relieving the clinical presentations. (15,16) However, its application in pediatric patients is yet to be confirmed. It has been reported that LT could be valuable when chronic liver failure or decompensated cirrhosis was indicated, although little is known about the longterm course of the disease after transplantation.…”

Quantitative Systems Pharmacology Modeling of Acid Sphingomyelinase Deficiency and the Enzyme Replacement Therapy Olipudase Alfa Is an Innovative Tool for Linking Pathophysiology and Pharmacology

“…Due to the mechanistic and multiscale nature of the ASMD QSP model, a diverse set of data sources was used to develop and calibrate the model ( Table ). These include natural history studies, in vitro cell line data, preclinical studies in the ASM knockout (ASMKO) mouse, and data from completed and ongoing clinical trials …”

“…ASM catalyzes the conversion of sphingomyelin, a major constituent of cell membranes, to ceramide. The reduced functional ASM leads to accumulation of sphingomyelin in multiple cell types, including cells of the monocyte‐macrophage lineage and hepatocytes . The consequent cell and tissue damage affects multiple organ systems, and causes heterogeneous disease manifestations, including, but not limited to, hepatosplenomegaly, infiltrative lung disease, hematological abnormalities, and dyslipidemia …”

“…By supplementing the deficient functional enzyme, ERTs for lysosomal storage diseases can clear the accumulated substrate and alleviate disease symptoms . A recent phase Ib trial of olipudase alfa included five adults and demonstrated improvements in multiple clinically relevant end points, including spleen volume, infiltrative lung disease, and in levels of stored sphingomyelin over 26 weeks of treatment . The ongoing, long‐term trial demonstrated that these patients continue to show clinical improvements in hepatosplenomegaly, infiltrative lung disease, and lipid profiles through 30 months of treatment .…”