TY - JOUR
T1 - Successful within-patient dose escalation of olipudase alfa in acid sphingomyelinase deficiency
AU - Wasserstein, Melissa P.
AU - Jones, Simon A.
AU - Soran, Handrean
AU - Diaz, George A.
AU - Lippa, Natalie
AU - Thurberg, Beth L.
AU - Culm-Merdek, Kerry
AU - Shamiyeh, Elias
AU - Inguilizian, Haig
AU - Cox, Gerald F.
AU - Puga, Ana Cristina
N1 - Publisher Copyright:
© 2015.
PY - 2015/9/1
Y1 - 2015/9/1
N2 - 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.
AB - 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.
KW - Dose escalation
KW - Niemann-Pick disease type B
KW - Nonneuronopathic ASMD
KW - Olipudase alfa
KW - Recombinant human acid sphingomyelinase
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U2 - 10.1016/j.ymgme.2015.05.013
DO - 10.1016/j.ymgme.2015.05.013
M3 - Article
C2 - 26049896
AN - SCOPUS:84940891469
SN - 1096-7192
VL - 116
SP - 88
EP - 97
JO - Molecular Genetics and Metabolism
JF - Molecular Genetics and Metabolism
IS - 1-2
ER -