Long-Term Miglustat Therapy in Children With Niemann-Pick Disease Type C

Abstract

Niemann-Pick disease type C is a rare, genetic disease associated with impaired intracellular lipid trafficking and progressive neurological symptoms. Miglustat slowed disease progression in a 12-month randomized trial in juveniles and adults with Niemann-Pick disease type C, and in a parallel, noncontrolled study in affected children. Here, the authors report the open-label extension to the pediatric study. Patients aged 4 to 12 years received open-label miglustat (dose adjusted for body surface area) for an initial 12 months, during a further 12-month extension, and a long-term, continued extension phase. Efficacy assessments included horizontal saccadic eye movement, swallowing, and ambulation. Ten children completed 24 months' treatment. Horizontal saccadic eye movement, ambulation, and swallowing were stabilized at 24 months. Analysis of key parameters of disease progression showed disease stability in 8 of 10 patients (80%). Miglustat stabilized neurological disease progression in pediatric patients with Niemann-Pick disease type C, with comparable safety and tolerability to that observed in adults and juveniles.

Miglustat Treatment May Reduce Cerebrospinal Fluid Levels of the Axonal Degeneration Marker Tau in Niemann–Pick Type C

“…This study exemplifies how small pilot studies may give information about biochemical drug effects in vivo in humans. Since miglustat may stabilize neurological symptoms in NPC (Patterson et al 2010;Wraith et al 2010), these data are encouraging and support the use of T-tau to detect effects on axonal degeneration in clinical trials for neurodegenerative diseases. The results may be interpreted in relation to prior observations on longitudinal T-tau measurements in other brain diseases.…”

“…Miglustat treatment seems to stabilize the neurological disease in a majority of NPC patients (Patterson et al 2007(Patterson et al , 2010Pineda et al 2009;Wraith et al 2010). However, diseasemonitoring may be difficult, and there is a need for improved biomarkers to identify treatment responders, and monitor progression and treatment effect (Galanaud et al 2009;Platt and Lachmann 2009).…”

Innovative Therapeutic Approaches for Improving Patient Life Condition with a Neurological Lysosomal Disease

“…Several clinical trials have since been conducted in humans using Miglustat, demonstrating mild clinical improvement or stabilization, with greater impact on earlier diagnosed populations. Miglustat is the only currently approved therapy for NPC disease and clearly slows disease progression with limited side effects Patterson et al, 2010;Galanaud et al, 2009;Patterson et al, 2007).…”

Impact of selected inborn errors of metabolism on prenatal and neonatal development

“…The recent approval of miglustat (N-butyldeoxynojirimycin; NBDNJ; Zavesca 1 , Actelion Pharmaceuticals Ltd.), is a significant step foward (49)(50)(51). Miglustat is a small iminosugar that acts as a chaperone and is a competitive inhibitor of the enzyme glucosylceramide synthase, which catalyses the first committed step in glycosphingolipid synthesis, resulting in ''substrate'' reduction.…”