Clearance of Hepatic Sphingomyelin by Olipudase Alfa is Associated with Improvement in Lipid Profiles in Acid Sphingomyelinase Deficiency

Beth L. Thurberg, Melissa P. Wasserstein, Simon A. Jones, Thomas D. Schiano, Gerald F. Cox, Ana Cristina Puga

Research output: Contribution to journalArticle

5 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1232-1242
Number of pages11
JournalAmerican Journal of Surgical Pathology
Volume40
Issue number9
DOIs
StatePublished - Sep 1 2016

Fingerprint

Type A Niemann-Pick Disease
Sphingomyelins
Lipids
Acids
Liver
Biopsy
Liver Function Tests
Type B Niemann-Pick Disease
Fibrosis
Biomarkers
Enzyme Replacement Therapy
Investigational Therapies
Kupffer Cells
Hepatomegaly
olipudase alfa
Liver Cirrhosis
Biochemistry
Hepatocytes
Electron Microscopy
Inflammation

Keywords

  • enzyme replacement therapy
  • hyperlipidemia
  • liver pathology
  • lysosomal storage disease
  • Niemann-Pick disease type B

ASJC Scopus subject areas

  • Anatomy
  • Surgery
  • Pathology and Forensic Medicine

Cite this

Clearance of Hepatic Sphingomyelin by Olipudase Alfa is Associated with Improvement in Lipid Profiles in Acid Sphingomyelinase Deficiency. / Thurberg, Beth L.; Wasserstein, Melissa P.; Jones, Simon A.; Schiano, Thomas D.; Cox, Gerald F.; Puga, Ana Cristina.

In: American Journal of Surgical Pathology, Vol. 40, No. 9, 01.09.2016, p. 1232-1242.

Research output: Contribution to journalArticle

Thurberg, Beth L. ; Wasserstein, Melissa P. ; Jones, Simon A. ; Schiano, Thomas D. ; Cox, Gerald F. ; Puga, Ana Cristina. / Clearance of Hepatic Sphingomyelin by Olipudase Alfa is Associated with Improvement in Lipid Profiles in Acid Sphingomyelinase Deficiency. In: American Journal of Surgical Pathology. 2016 ; Vol. 40, No. 9. pp. 1232-1242.
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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.",
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