Medication Summary
The first disease-specific enzyme replacement treatment for non-CNS ASMD, olipudase alfa, was approved by the FDA in August 2022. Gene therapies, enzyme replacement therapies, and bone marrow transplantations have been studied in animal models, but the challenge is to deliver treatments directly into the central nervous system (CNS) before the onset of neurologic symptoms. Safety assessment of intracranial injection of biologic vectors into the brain is still under discussion. [2]
Early clinical trails of recombinant human ASM (rhASM) treatment for non-neurologic manifestations were encouraging. [23, 24, 25] Recombinant human ASM has been successfully produced in Chinese hamster ovary cells. Initial treatment studies were conducted in animal models, specifically, in ASM knockout mice. Treatment with rhASM in these animals resulted in dose-dependent toxicity. Such toxicity could be prevented by dose escalation to debulk stored sphingomyelin and thus maintain a low level of ceramide release.
Subsequent studies have begun in humans. In a phase 1 study in adult patients, single administrations of rhASM (olipudase alfa) in increasing doses once every 2 weeks were undertaken, without adverse events. A 0.6 mg/kg maximum starting dose was determined. Transient elevation of cytokines and bilirubin was observed in this cohort. [24] In Phase 1b, a dose escalation scheme was used in five adult patients, first with low doses to debulk sphingomyelin in tissues, then with dose escalations of up to 3 mg/kg, for a total of 26 weeks. No serious adverse events were encountered. [23]
Miglustat is used off-label in the United States for NPD type C. It is approved for NPD type C in Australia, Canada, New Zealand, and several countries in Asia, Europe, and South America. [26]
Enzymes, Metabolic
Class Summary
A decrease in the activity of the enzyme acid sphingomyelinase (ASM), resulting from pathogenic variants in the sphingomyelin phosphodiesterase 1 gene, causes the lysosomal storage disease ASM deficiency (ASMD). Sphingomyelin is degraded to ceramide and phosphocholine by ASM. Intra-lysosomal accumulation of sphingomyelin (along with cholesterol and other cell membrane lipids) develops in various tissues as a consequence of ASMD.
Olipudase alfa (Xenpozyme)
Olipudase alfa is a recombinant ASM enzyme that the FDA has approved for the treatment of non–central nervous system manifestations of ASMD in adult and pediatric patients.
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Autosomal recessive inheritance pattern.
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Role of acid sphingomyelinase in metabolism pathways inside cellular organelles.
