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.