Abstract
Olipudase alfa, a recombinant human acid sphingomyelinase (ASM), is an enzyme replacement therapy for the treatment of nonneurologic manifestations of acid sphingomyelinase deficiency (ASMD). This ongoing, open-label, long-term study (NCT02004704) assessed safety and efficacy of olipudase alfa following 30 months of treatment in five adult patients with ASMD. There were no deaths, serious or severe events, or discontinuations during 30 months of treatment. The majority of adverse events were mild and included headache, nausea, and abdominal pain. No patient developed anti-drug antibodies and there were no clinically significant adverse changes in vital signs, hematology, or cardiac safety parameters. Statistically significant reductions in liver (31%) and spleen (39%) volumes were maintained through 30 months of treatment. There was a mean increase in lung diffusing capacity of 35%, and clinically relevant improvements in infiltrative lung disease parameters. Lipid profiles improved in all patients. Improvements in bone mineral density of the spine were observed in some patients. Chitotriosidase in serum and lyso-sphingomyelin in dried blood spots decreased with olipudase alfa treatment, suggesting utility as biomarkers for monitoring treatment efficacy. Olipudase alfa is the first etiology-specific treatment in development for ASMD. This study demonstrates that treatment with olipudase alfa for 30 months is well-tolerated and associated with life-transforming sustained improvements in relevant disease clinical measures.
Highlights
Acid sphingomyelinase deficiency (ASMD), an autosomal recessive lysosomal storage disorder, results from mutations in the SMPD1 gene encoding the lysosomal enzyme acid sphingomyelinase (ASM) (Schuchman and Desnick 2017)
Long-term safety and efficacy of olipudase alfa continue to be assessed in these patients, and the present analysis shows a sustained safety profile and continued improvements in multiple clinically relevant parameters following 30 months of treatment
This ongoing, open-label, long-term study (LTS) (NCT02004704; EudraCT Number: 2013–000051-40) follows five adult patients with chronic ASMD who previously participated in the phase 1b study (Wasserstein et al 2015)
Summary
Acid sphingomyelinase deficiency (ASMD), an autosomal recessive lysosomal storage disorder, results from mutations in the SMPD1 gene encoding the lysosomal enzyme acid sphingomyelinase (ASM) (Schuchman and Desnick 2017). Subsequent sphingomyelin accumulation in multiple organs causes visceral disease and neurodegeneration in severe cases. Infantile neurovisceral ASMD (historically known as Niemann-Pick disease type A [NPD A]), the most severe disease phenotype, results in death in early childhood (McGovern et al 2006). Morbidity from liver, lung, and hematologic disease occurs in all patients with chronic ASMD and includes hepatosplenomegaly, liver dysfunction, infiltrative lung disease, and thrombocytopenia (McGovern et al 2013, McGovern et al 2017). Growth restriction during childhood and bone disease are common features of chronic ASMD (Wasserstein et al 2003). Pulmonary and liver disease are the main causes of death in these patients (McGovern et al 2008, Cassiman et al 2016)
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