Elsevier

Molecular Genetics and Metabolism

Volume 116, Issues 1–2, September–October 2015, Pages 88-97
Molecular Genetics and Metabolism

Successful within-patient dose escalation of olipudase alfa in acid sphingomyelinase deficiency

https://doi.org/10.1016/j.ymgme.2015.05.013Get rights and content
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Highlights

  • Olipudase alfa is an ERT in development for ASMD.

  • Within-patient, dose-escalation was used to debulk accumulated sphingomyelin.

  • This novel dosing regimen enabled safe, tolerable, and effective repeat dosing.

Abstract

Background

Olipudase alfa, a recombinant human acid sphingomyelinase (rhASM), is an investigational enzyme replacement therapy (ERT) for patients with ASM deficiency [ASMD; Niemann–Pick Disease (NPD) A and B]. This open-label phase 1b study assessed the safety and tolerability of olipudase alfa using within-patient dose escalation to gradually debulk accumulated sphingomyelin and mitigate the rapid production of metabolites, which can be toxic. Secondary objectives were pharmacokinetics, pharmacodynamics, and exploratory efficacy.

Methods

Five adults with nonneuronopathic ASMD (NPD B) received escalating doses (0.1 to 3.0 mg/kg) of olipudase alfa intravenously every 2 weeks for 26 weeks.

Results

All patients successfully reached 3.0 mg/kg without serious or severe adverse events. One patient repeated a dose (2.0 mg/kg) and another had a temporary dose reduction (1.0 to 0.6 mg/kg). Most adverse events (97%) were mild and all resolved without sequelae. The most common adverse events were headache, arthralgia, nausea and abdominal pain. Two patients experienced single acute phase reactions. No patient developed hypersensitivity or anti-olipudase alfa antibodies. The mean circulating half-life of olipudase alfa ranged from 20.9 to 23.4 h across doses without accumulation. Ceramide, a sphingomyelin catabolite, rose transiently in plasma after each dose, but decreased over time. Reductions in sphingomyelin storage, spleen and liver volumes, and serum chitotriosidase activity, as well as improvements in infiltrative lung disease, lipid profiles, platelet counts, and quality of life assessments, were observed.

Conclusions

This study provides proof-of-concept for the safety and efficacy of within-patient dose escalation of olipudase alfa in patients with nonneuronopathic ASMD.

Keywords

Olipudase alfa
Recombinant human acid sphingomyelinase
Dose escalation
Nonneuronopathic ASMD
Niemann–Pick disease type B

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Trial registration: Clintrials.gov trial registration # NCT01722526.