Olipudase alfa for treatment of acid sphingomyelinase deficiency (ASMD): safety and efficacy in adults treated for 30 months

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.Electronic supplementary materialThe online version of this article (10.1007/s10545-017-0123-6) contains supplementary material, which is available to authorized users.

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

“…The organ‐level submodel was calibrated to clinical measurements of spleen volume and Hb‐adjusted % predicted DLco ( Figure ). Improvements in both clinical end points over the course of the phase Ib study and its long‐term extension are clinically meaningful . The model captures the individual‐specific improvement in spleen volume and Hb‐adjusted % predicted DLco, recapitulating the data well even across varying initial severities in the two clinical manifestations.…”

“…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 …”

“…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 . A phase II/III adult trial (http://ClinicalTrials.gov Identifier: NCT02004691; clinicaltrialsregister.eu EudraCT number: 2015‐000371‐26) and phase I/II pediatric trial (http://ClinicalTrials.gov Identifier: NCT02292654; clinicaltrialsregister.eu EudraCT Number: 2014–003198‐40) for olipudase alfa are currently ongoing.…”

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.…”