BACKGROUND:Niemann-Pick type C disease (NPC) is an inherited neurodegenerative disorder characterised by an intracellular lipid-trafficking defect with secondary accumulation of glycosphingolipids. Miglustat, a small iminosugar, reversibly inhibits glucosylceramide synthase, which catalyses the first committed step of glycosphingolipid synthesis. Miglustat is able to cross the blood-brain barrier, and is thus a potential therapy for neurological diseases. We aimed to establish the effect of miglustat on several markers of NPC severity. METHODS:Patients aged 12 years or older who had NPC (n=29) were randomly assigned to receive either miglustat 200 mg three times a day (n=20) or standard care (n=9) for 12 months. 12 children younger than 12 years of age were included in an additional cohort; all received miglustat at a dose adjusted for body surface area. All participants were then treated with miglustat for an additional year in an extension study. The primary endpoint was horizontal saccadic eye movement (HSEM) velocity, based on its correlation with disease progression. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN26761144. FINDINGS: At 12 months, HSEM velocity had improved in patients treated with miglustat versus those receiving standard care; results were significant when patients taking benzodiazepines were excluded (p=0.028). Children showed an improvement in HSEM velocity of similar size at 12 months. Improvement in swallowing capacity, stable auditory acuity, and a slower deterioration in ambulatory index were also seen in treated patients older than 12 years. The safety and tolerability of miglustat 200 mg three times a day in study participants was consistent with previous trials in type I Gaucher disease, where half this dose was used. INTERPRETATION:Miglustat improves or stabilises several clinically relevant markers of NPC. This is the first agent studied in NPC for which there is both animal and clinical data supporting a disease modifying benefit.
RCT Entities:
BACKGROUND:Niemann-Pick type C disease (NPC) is an inherited neurodegenerative disorder characterised by an intracellular lipid-trafficking defect with secondary accumulation of glycosphingolipids. Miglustat, a small iminosugar, reversibly inhibits glucosylceramide synthase, which catalyses the first committed step of glycosphingolipid synthesis. Miglustat is able to cross the blood-brain barrier, and is thus a potential therapy for neurological diseases. We aimed to establish the effect of miglustat on several markers of NPC severity. METHODS:Patients aged 12 years or older who had NPC (n=29) were randomly assigned to receive either miglustat 200 mg three times a day (n=20) or standard care (n=9) for 12 months. 12 children younger than 12 years of age were included in an additional cohort; all received miglustat at a dose adjusted for body surface area. All participants were then treated with miglustat for an additional year in an extension study. The primary endpoint was horizontal saccadic eye movement (HSEM) velocity, based on its correlation with disease progression. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN26761144. FINDINGS: At 12 months, HSEM velocity had improved in patients treated with miglustat versus those receiving standard care; results were significant when patients taking benzodiazepines were excluded (p=0.028). Children showed an improvement in HSEM velocity of similar size at 12 months. Improvement in swallowing capacity, stable auditory acuity, and a slower deterioration in ambulatory index were also seen in treated patients older than 12 years. The safety and tolerability of miglustat 200 mg three times a day in study participants was consistent with previous trials in type I Gaucher disease, where half this dose was used. INTERPRETATION: Miglustat improves or stabilises several clinically relevant markers of NPC. This is the first agent studied in NPC for which there is both animal and clinical data supporting a disease modifying benefit.
Authors: Xuntian Jiang; Rohini Sidhu; Forbes D Porter; Nicole M Yanjanin; Anneliese O Speak; Danielle Taylor te Vruchte; Frances M Platt; Hideji Fujiwara; David E Scherrer; Jessie Zhang; Dennis J Dietzen; Jean E Schaffer; Daniel S Ory Journal: J Lipid Res Date: 2011-04-24 Impact factor: 5.922
Authors: Jessica Davidson; Elizabeth Molitor; Samantha Moores; Sarah E Gale; Kanagaraj Subramanian; Xuntian Jiang; Rohini Sidhu; Pamela Kell; Jesse Zhang; Hideji Fujiwara; Cristin Davidson; Paul Helquist; Bruce J Melancon; Michael Grigalunas; Gang Liu; Farbod Salahi; Olaf Wiest; Xin Xu; Forbes D Porter; Nina H Pipalia; Dana L Cruz; Edward B Holson; Jean E Schaffer; Steven U Walkley; Frederick R Maxfield; Daniel S Ory Journal: Biochim Biophys Acta Mol Cell Biol Lipids Date: 2019-04-30 Impact factor: 4.698